Novel opioid antagonists

ABSTRACT

Certain quinolizidine and octahydropyridopyrazine compounds, pharmaceutical compositions, and methods of their use, inter alia, as opioid receptor antagonists are disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. application Ser.No. 12/463,814, filed May 11, 2009, which is a divisional application ofU.S. Pat. No. 7,538,110, issued May 26, 2009, which claims the benefitof U.S. Provisional Application Ser. No. 60/730,609, filed Oct. 27,2005, the disclosure of each of which is hereby incorporated herein byreference in its entirety.

FIELD OF THE INVENTION

The invention relates to compounds that affect the opioid receptorsystem and, more particularly, to quinolizidine andoctahydropyridopyrazine compounds, pharmaceutical compositionscontaining such compounds that are, inter alia, antagonists of opioidreceptors, and methods of their use.

BACKGROUND OF THE INVENTION

It is well known that opioid drugs target three types of endogenousopioid receptors (i.e., μ, δ, and κ receptors) in biological systems.Many opiates, such as morphine, are μ opioid agonists that are oftenused as analgesics for the treatment of severe pain due to theiractivation of μ opioid receptors in the brain and central nervous system(CNS). Opioid receptors are, however, not limited to the CNS, and may befound in other tissues throughout the body, i.e., peripheral to the CNS.A number of side effects of opioid drugs may be caused by activation ofthese peripheral receptors. For example, administration of μ opioidagonists often results in intestinal dysfunction due to the large numberof receptors in the wall of the gut (Wittert, G., Hope, P. and Pyle, D.,Biochemical and Biophysical Research Communications, 1996, 218, 877-881;Bagnol, D., Mansour, A., Akil, A. and Watson, S. J., Neuroscience, 1997,81, 579-591). Specifically, opioids are generally known to cause nauseaand vomiting, as well as inhibition of normal propulsivegastrointestinal function in animals and man (Reisine, T., andPasternak, G., Goodman & Gilman's The Pharmacological Basis ofTherapeutics, Ninth Edition, 1996, 521-555), resulting in side effectssuch as, for example, constipation.

Recent evidence has indicated that naturally-occurring endogenous opioidcompounds may also affect propulsive activity in the gastrointestinal(GI) tract. Met-enkephalin, which activates μ and δ receptors in boththe brain and gut, is one of several neuropeptides found in the GI tract(Koch, T. R., Carney, J. A., Go, V. L., and Szurszewski, J. H.,Digestive Diseases and Sciences, 1991, 36, 712-728). Additionally,receptor knockout techniques have shown that mice lacking μ opioidreceptors may have faster GI transit times than wild-type mice,suggesting that endogenous opioid peptides may tonically inhibit GItransit in normal mice (Schuller, A. G. P., King, M., Sherwood, A. C.,Pintar, J. E., and Pasternak, G. W., Society of Neuroscience Abstracts1998, 24, 524). Studies have shown that opioid peptides and receptorslocated throughout the GI tract may be involved in normal regulation ofintestinal motility and mucosal transport of fluids in both animals andman (Reisine, T., and Pasternak, G., Goodman & Gilman's ThePharmacological Basis of Therapeutics, Ninth Edition, 1996, 521-555).Other studies show that the sympathetic nervous system may be associatedwith endogenous opioids and control of intestinal motility (Bagnol, D.,Herbrecht, F., Jule, Y., Jarry, T., and Cupo, A., Regul. Pept., 1993,47, 259-273). The presence of endogenous opioid compounds associatedwith the GI tract suggests that an abnormal physiological level of thesecompounds may lead to bowel dysfunction.

It is a common problem for patients having undergone surgicalprocedures, especially surgery of the abdomen, to suffer from aparticular bowel dysfunction called post-surgical (or post-operative)ileus. “Ileus,” as used herein, refers to the obstruction of the bowelor gut, especially the colon. See, e.g., Dorland's Illustrated MedicalDictionary, 27th ed., page 816, (W.B. Saunders Company, Philadelphia,Pa., 1988). Ileus should be distinguished from constipation, whichrefers to infrequency of or difficulty in feces evacuation. See, e.g.,Dorland's Illustrated Medical Dictionary, 27th ed., page 375, (W. B.Saunders Company, Philadelphia, 1988). Ileus may be diagnosed by thedisruption of normal coordinated movements of the gut, resulting infailure of intestinal contents propulsion. See, e.g., Resnick, J., Am.J. of Gastroenterology, 1997, 92, 751 and Resnick, J. Am. J. ofGastroenterology, 1997, 92, 934. In some instances, particularlyfollowing surgery, including surgery of the abdomen, the boweldysfunction may become quite severe, lasting for more than a week andaffecting more than one portion of the GI tract. This condition is oftenreferred to as post-surgical (or post-operative) paralytic ileus andmost frequently occurs after laparotomy (see Livingston, E. H. andPassaro, Jr., E. D., Digestive Diseases and Sciences, 1990, 35, 121).Similarly, post-partum ileus is a common problem for women in the periodfollowing childbirth, and is thought to be caused by similarfluctuations in natural opioid levels as a result of birthing stress.

Gastrointestinal dysmotility associated with post-surgical ileus isgenerally most severe in the colon and typically lasts for 3 to 5 days.The administration of opioid analgesics to a patient after surgery mayoften contribute to bowel dysfunction, thereby delaying recovery ofnormal bowel function. Since virtually all patients receive opioidanalgesics, such as morphine or other narcotics, for pain relief aftersurgery, particularly major surgery, current post-surgical paintreatment may actually slow recovery of normal bowel function, resultingin a delay in hospital discharge and increasing the cost of medicalcare.

Post-surgical and post-partum ileus may also occur in the absence ofexogenous opioid agonists. It would be of benefit to inhibit the naturalactivity of endogenous opioids during and/or after periods of biologicalstress, such as surgery and childbirth, so that ileus and related formsof bowel dysfunction can be prevented and/or treated. Currently,therapies for ileus include functional stimulation of the intestinaltract, stool softeners, laxatives, lubricants, intravenous hydration,and nasogastric decompression. These prior art methods suffer fromdrawbacks, for example, as lacking specificity for post-surgical orpost-partum ileus. And these prior art methods offer no means forprevention. If ileus could be prevented, hospital stays, recovery times,and medical costs would be significantly decreased, in addition to thebenefit of minimizing patient discomfort. Thus, drugs that selectivelyact on opioid receptors in the gut would be ideal candidates forpreventing and/or treating post-surgical and post-partum ileus. Ofthose, drugs that do not interfere with the effects of opioid analgesicsin the CNS would be of special benefit in that they could beadministered simultaneously for pain management with limited sideeffects.

Peripheral opioid antagonists that do not cross the blood-brain barrierinto the CNS are known in the literature and have been tested inrelation to their activity on the GI tract. In U.S. Pat. No. 5,250,542,U.S. Pat. No. 5,434,171, U.S. Pat. No. 5,159,081, and U.S. Pat. No.5,270,328, peripherally selective piperidine-N-alkylcarboxylate opioidantagonists are described as being useful in the treatment of idiopathicconstipation, irritable bowel syndrome, and opioid-induced constipation.In addition, U.S. Pat. No. 4,176,186 describes quaternary derivatives ofnoroxymorphone (i.e., methylnaltrexone) that are said to prevent orrelieve the intestinal immobility side effect of narcotic analgesicswithout reducing analgesic effectiveness. U.S. Pat. No. 5,972,954describes the use of methylnaltrexone, enteric-coated methylnaltrexone,or other quaternary derivatives of noroxymorphone for preventing and/ortreating opioid- and/or non-opioid-induced side effects associated withopioid administration.

General opioid antagonists, such as naloxone and naltrexone, have alsobeen implicated as being useful in the treatment of GI tractdysmotility. For example, U.S. Pat. No. 4,987,126 and Kreek, M. J.,Schaefer, R. A., Hahn, E. F., Fishman, J. Lancet, 1983, 1, 8319, 261disclose naloxone and other morphinan-based opioid antagonists (i.e.,naltrexone) for the treatment of idiopathic gastrointestinaldysmotility. In addition, naloxone has been shown to effectively treatnon-opioid induced bowel obstruction, implying that the drug may actdirectly on the GI tract or in the brain (Schang, J. C., Devroede, G.,Am. J. Gastroenterol., 1985, 80, 6, 407). Furthermore, it has beenimplicated that naloxone may provide therapy for paralytic ileus (Mack,D. J. Fulton, J. D., Br. J. Surg., 1989, 76, 10, 1101). However, it iswell known that activity of naloxone and related drugs is not limited toperipheral systems and may interfere with the analgesic effects ofopioid narcotics.

Alvimopan is an orally active, gastrointestinal (GI) restricted μ opioidantagonist being developed to alleviate the GI side effects associatedwith narcotic therapy. Alvimopan inhibits [³H]diprenorphine binding tocloned human opioid receptors with K_(i) values of 0.44 nM, 10 nM and 92nM for μ, δ, and κ receptors respectively. This compound differs frompreviously characterized peripherally selective opioid antagonists byits potency and degree of peripheral receptor selectivity [Zimmerman, etal., J. Med. Chem., 1994, 37, 2262-2265].

The μ opioid antagonist family of trans-3,4-dimethyl-4-phenylpiperidineshas been indicated as food consumption reducing agents [W. N. Shaw, etal., J. Pharm. and Exp. Ther., 1990, 253(1), 85-89]. Long-term chronicadministration significantly reduced food consumption in obese testanimals for as long as a phenylpiperidine μ opioid antagonist wasadministered, resulting in a significant decrease in weight gaincompared to control. Accordingly, compounds with μ opioid antagonistproperties are likely to have benefit in the treatment or management ofobesity in patients, especially those non-zwitterionic compounds thatwould be able to cross the blood-brain barrier.

Inasmuch as post-surgical and post-partum ileus, for example, are commonillnesses that add to the cost of health care and as yet have nospecific treatment, there is a need for a specific and effective remedy.The majority of currently known opioid antagonist therapies are notperipherally selective and have the potential for undesirable sideeffects resulting from penetration into the CNS. Given the estimated 21million inpatient surgeries and 26 million outpatient surgeries eachyear, and an estimate of 4.7 million patients experiencing post-surgicalileus, methods involving opioid antagonists that are not only specificfor peripheral systems, but also specific for the gut, are desirable fortreating post-surgical and post-partum ileus.

There is still an unfulfilled need for compounds that may be used inmethods to antagonize opioid receptors, particularly where undesirablesymptoms or conditions are side effects of administering exogenousopioids. The present invention is directed to these, as well as otherimportant ends.

SUMMARY OF THE INVENTION

The present invention is generally directed to quinolizidine andoctahydropyridopyrazine derivatives, pharmaceutical compositionscontaining these compounds, and methods of their pharmaceutical use.

In one embodiment, the invention is directed to compounds of formula I:

-   -   wherein:        -   R¹ is —OH, —OR^(a), —CH₂OH, —C(═O)OR⁶, —C(═O)NR⁶R⁷, or            —NR⁶R⁷;        -   R² and R³ are each independently alkyl or alkenyl;        -   R⁴ is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl,            heteroaryl, aralkyl, alkylaralkyl, or heteroarylalkyl;        -   X is CH₂ or NR⁵;        -   R⁵ is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl,            heteroaryl, aralkyl, alkylaralkyl, heteroarylalkyl,            —C(═O)OR^(8a), —S(═O)₂R^(8a), —C(═O)R^(8b), or            —C(═O)NR^(8b)R^(8c);        -   R⁶ is H, alkyl, cycloalkyl, alkylcycloalkyl, or aralkyl;        -   R⁷ is H, alkyl, aralkyl, or aryl;        -   R^(8a) is alkyl, cycloalkyl, cycloalkylalkyl, heteroaryl,            heteroarylalkyl, aralkyl, or aryl;        -   R^(8b) and R^(8c) are each independently H, alkyl,            cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl,            aralkyl, or aryl; or R^(8b) and R^(8c) taken together with            the nitrogen atom to which they are connected form a 4- to            8-membered heterocycloalkyl ring;        -   R^(a) is a hydroxyl protecting group;        -   m is 1 or 2; and        -   n is 0, 1, or 2;        -   with the provisos that:            -   at least one of m and n is other than 2; and            -   when X is NR⁵, then n is 1 or 2;        -   or a pharmaceutically acceptable salt thereof.

In another embodiment, the invention is directed to compounds of formulaIII:

-   -   wherein:        -   R¹ is —OH, —OR^(a), —CH₂OH, —C(═O)OR⁶, —C(═O)NR⁶R⁷, or            —NR⁶R⁷;        -   R² and R³ are each independently alkyl or alkenyl;        -   R⁴ is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl,            heteroaryl, aralkyl, alkylaralkyl, or heteroarylalkyl;        -   X is CH₂ or NR⁵;        -   R⁵ is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl,            heteroaryl, aralkyl, alkylaralkyl, heteroarylalkyl,            heterocycloalkylalkyl, —C(═O)OR^(8a), —S(═O)₂R^(8a),            —C(═O)R^(8b), or —C(═O)NR^(8b)R^(8c);        -   R⁶ is H, alkyl, cycloalkyl, alkylcycloalkyl, or aralkyl;        -   R⁷ is H, alkyl, aralkyl, or aryl;        -   R^(8a) is alkyl, cycloalkyl, cycloalkylalkyl, heteroaryl,            heteroarylalkyl, aralkyl, or aryl;        -   R^(8b) and R^(8c) are each independently H, alkyl,            cycloalkyl, cycloalkylalkyl, heteroaryl, heterocycloalkyl,            heterocycloalkylalkyl, heteroarylalkyl, aralkyl, or aryl; or            R^(8b) and R^(8c) taken together with the nitrogen atom to            which they are connected form a 4- to 8-membered            heterocycloalkyl ring;        -   R^(a) is a hydroxyl protecting group;        -   m is 1 or 2; and        -   n is 0, 1, or 2;        -   with the provisos that:            -   at least one of m and n is other than 2; and            -   when X is NR⁵, then n is 1 or 2;        -   or a pharmaceutically acceptable salt thereof.

In still another embodiment, the invention is directed to pharmaceuticalcompositions comprising:

a pharmaceutically acceptable carrier; and

an effective amount of a compound of the invention, preferably acompound of formula Ia:

-   -   wherein:        -   R¹ is —OH, —CH₂OH, —C(═O)OR⁶, —C(═O)NR⁶R⁷, or —NR⁶R⁷;        -   R² and R³ are each independently alkyl or alkenyl;        -   R⁴ is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl,            heteroaryl, aralkyl, alkylaralkyl, or heteroarylalkyl;        -   X is CH₂ or NR⁵;        -   R⁵ is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl,            heteroaryl, aralkyl, alkylaralkyl, heteroarylalkyl,            —C(═O)OR^(8a), —S(═O)₂R^(8a), —C(═O)R^(8b), or            —C(═O)NR^(8b)R^(8c);        -   R⁶ is H, alkyl, cycloalkyl, alkylcycloalkyl, or aralkyl;        -   R⁷ is H, alkyl, aralkyl, or aryl;        -   R^(8a) is alkyl, cycloalkyl, cycloalkylalkyl, heteroaryl,            heteroarylalkyl, aralkyl, or aryl;        -   R^(8b) and R^(8c) are each independently H, alkyl,            cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl,            aralkyl, or aryl; or R^(8b) and R^(8c) taken together with            the nitrogen atom to which they are connected form a 4- to            8-membered heterocycloalkyl ring;        -   m is 1 or 2; and        -   n is 0, 1, or 2;        -   with the provisos that:            -   at least one of m and n is other than 2; and            -   when X is NR⁵, then n is 1 or 2;        -   or a pharmaceutically acceptable salt thereof.

In another embodiment, the invention is directed to pharmaceuticalcompositions comprising:

a pharmaceutically acceptable carrier; and

an effective amount of a compound of the invention, preferably acompound of formula IIIa:

-   -   wherein:        -   R¹ is —OH, —CH₂OH, —C(═O)OR⁶, —C(═O)NR⁶R⁷, or —NR⁶R⁷;        -   R² and R³ are each independently alkyl or alkenyl;        -   R⁴ is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl,            heteroaryl, aralkyl, alkylaralkyl, or heteroarylalkyl;        -   X is CH₂ or NR⁵;        -   R⁵ is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl,            heteroaryl, aralkyl, alkylaralkyl, heteroarylalkyl,            heterocycloalkylalkyl, —C(═O)OR^(8a), —S(═O)₂R^(8a),            —C(═O)R^(8b), or —C(═O)NR^(8b)R^(8c);        -   R⁶ is H, alkyl, cycloalkyl, alkylcycloalkyl, or aralkyl;        -   R⁷ is H, alkyl, aralkyl, or aryl;        -   R^(8a) is alkyl, cycloalkyl, cycloalkylalkyl, heteroaryl,            heteroarylalkyl, aralkyl, or aryl;        -   R^(8b) and R^(8c) are each independently H, alkyl,            cycloalkyl, cycloalkylalkyl, heteroaryl, heterocycloalkyl,            heterocycloalkyl, heteroarylalkyl, aralkyl, or aryl; or            R^(8b) and R^(8c) taken together with the nitrogen atom to            which they are connected form a 4- to 8-membered            heterocycloalkyl ring;        -   m is 1 or 2; and        -   n is 0, 1, or 2;        -   with the provisos that:            -   at least one of m and n is other than 2; and            -   when X is NR⁵, then n is 1 or 2;        -   or a pharmaceutically acceptable salt thereof.

In yet another embodiment, the invention is directed to methods forbinding opioid receptors, in a patient in need thereof, comprising thestep of:

administering to the patient a composition comprising an effectiveamount of a compound of the invention, preferably a compound of formulaIa:

-   -   wherein:        -   R¹ is —OH, —CH₂OH, —C(═O)OR⁶, —C(═O)NR⁶R⁷, or —NR⁶R⁷;        -   R² and R³ are each independently alkyl or alkenyl;        -   R⁴ is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl,            heteroaryl, aralkyl, alkylaralkyl, or heteroarylalkyl;        -   X is CH₂ or NR⁵;        -   R⁵ is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl,            heteroaryl, aralkyl, alkylaralkyl, heteroarylalkyl,            —C(═O)OR^(8a), —S(═O)₂R^(8a), —C(═O)R^(8b), or            —C(═O)NR^(8b)R^(8c);        -   R⁶ is H, alkyl, cycloalkyl, alkylcycloalkyl, or aralkyl;        -   R⁷ is H, alkyl, aralkyl, or aryl;        -   R^(8a) is alkyl, cycloalkyl, cycloalkylalkyl, heteroaryl,            heteroarylalkyl, aralkyl, or aryl;        -   R^(8b) and R^(8c) are each independently H, alkyl,            cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl,            aralkyl, or aryl; or R^(8b) and R^(8c) taken together with            the nitrogen atom to which they are connected form a 4- to            8-membered heterocycloalkyl ring;        -   m is 1 or 2; and        -   n is 0, 1, or 2;        -   with the provisos that:            -   at least one of m and n is other than 2; and            -   when X is NR⁵, then n is 1 or 2;        -   or a pharmaceutically acceptable salt thereof.

In other embodiments, the invention is directed to methods of treatinggastrointestinal dysfunction, comprising the step of:

administering to a patient in need thereof, a composition comprising aneffective amount of a compound of the invention, preferably a compoundof formula Ia:

-   -   wherein:        -   R¹ is —OH, —CH₂OH, —C(═O)OR⁶, —C(═O)NR⁶R⁷, or —NR⁶R⁷;        -   R² and R³ are each independently alkyl or alkenyl;        -   R⁴ is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl,            heteroaryl, aralkyl, alkylaralkyl, or heteroarylalkyl;        -   X is CH₂ or NR⁵;        -   R⁵ is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl,            heteroaryl, aralkyl, alkylaralkyl, heteroarylalkyl,            —C(═O)OR^(8a), —S(═O)₂R^(8a), —C(═O)R^(8b), or            —C(═O)NR^(8b)R^(8c);        -   R⁶ is H, alkyl, cycloalkyl, alkylcycloalkyl, or aralkyl;        -   R⁷ is H, alkyl, aralkyl, or aryl;        -   R^(8a) is alkyl, cycloalkyl, cycloalkylalkyl, heteroaryl,            heteroarylalkyl, aralkyl, or aryl;        -   R^(8b) and R^(8c) are each independently H, alkyl,            cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl,            aralkyl, or aryl; or R^(8b) and R^(8c) taken together with            the nitrogen atom to which they are connected form a 4- to            8-membered heterocycloalkyl ring;        -   m is 1 or 2; and        -   n is 0, 1, or 2;        -   with the provisos that:            -   at least one of m and n is other than 2; and            -   when X is NR⁵, then n is 1 or 2;        -   or a pharmaceutically acceptable salt thereof.

In yet other embodiments, the invention is directed to methods oftreating ileus, comprising the step of:

administering to a patient in need thereof, a composition comprising aneffective amount of a compound of the invention, preferably a compoundof formula Ia:

-   -   wherein:        -   R¹ is —OH, —CH₂OH, —C(═O)OR⁶, —C(═O)NR⁶R⁷, or —NR⁶R⁷;        -   R² and R³ are each independently alkyl or alkenyl;        -   R⁴ is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl,            heteroaryl, aralkyl, alkylaralkyl, or heteroarylalkyl;        -   X is CH₂ or NR⁵;        -   R⁵ is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl,            heteroaryl, aralkyl, alkylaralkyl, heteroarylalkyl,            —C(═O)OR^(8a), —S(═O)₂R^(8a), —C(═O)R^(8b), or            —C(═O)NR^(8b)R^(8c);        -   R⁶ is H, alkyl, cycloalkyl, alkylcycloalkyl, or aralkyl;        -   R⁷ is H, alkyl, aralkyl, or aryl;        -   R^(8a) is alkyl, cycloalkyl, cycloalkylalkyl, heteroaryl,            heteroarylalkyl, aralkyl, or aryl;        -   R^(8b) and R^(8c) are each independently H, alkyl,            cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl,            aralkyl, or aryl; or R^(8b) and R^(8c) taken together with            the nitrogen atom to which they are connected form a 4- to            8-membered heterocycloalkyl ring;        -   m is 1 or 2; and        -   n is 0, 1, or 2;        -   with the provisos that:            -   at least one of m and n is other than 2; and            -   when X is NR⁵, then n is 1 or 2;        -   or a pharmaceutically acceptable salt thereof.

In still other embodiments, the invention is directed to methods oftreating obesity, comprising the step of:

administering to a patient in need thereof, a composition comprising aneffective amount of a compound of the invention, preferably a compoundof formula Ia:

-   -   wherein:        -   R¹ is —OH, —CH₂OH, —C(═O)OR⁶, —C(═O)NR⁶R⁷, or —NR⁶R⁷;        -   R² and R³ are each independently alkyl or alkenyl;        -   R⁴ is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl,            heteroaryl, aralkyl, alkylaralkyl, or heteroarylalkyl;        -   X is CH₂ or NR⁵;        -   R⁵ is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl,            heteroaryl, aralkyl, alkylaralkyl, heteroarylalkyl,            —C(═O)OR^(8a), —S(═O)₂R^(8a), —C(═O)R^(8b), or            —C(═O)NR^(8b)R^(8c);        -   R⁶ is H, alkyl, cycloalkyl, alkylcycloalkyl, or aralkyl;        -   R⁷ is H, alkyl, aralkyl, or aryl;        -   R^(8a) is alkyl, cycloalkyl, cycloalkylalkyl, heteroaryl,            heteroarylalkyl, aralkyl, or aryl;        -   R^(8b) and R^(8c) are each independently H, alkyl,            cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl,            aralkyl, or aryl; or R^(8b) and R^(8c) taken together with            the nitrogen atom to which they are connected form a 4- to            8-membered heterocycloalkyl ring;        -   m is 1 or 2; and        -   n is 0, 1, or 2;        -   with the provisos that:            -   at least one of m and n is other than 2; and            -   when X is NR⁵, then n is 1 or 2;        -   or a pharmaceutically acceptable salt thereof.

In another embodiment, the invention is directed to methods of treatinga side effect associated with an opioid, comprising the step of:

administering to a patient in need thereof, a composition comprising aneffective amount of a compound of the invention, preferably a compoundof formula Ia:

-   -   wherein:        -   R¹ is —OH, —CH₂OH, —C(═O)OR⁶, —C(═O)NR⁶R⁷, or —NR⁶R⁷;        -   R² and R³ are each independently alkyl or alkenyl;        -   R⁴ is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl,            heteroaryl, aralkyl, alkylaralkyl, or heteroarylalkyl;        -   X is CH₂ or NR⁵;        -   R⁵ is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl,            heteroaryl, aralkyl, alkylaralkyl, heteroarylalkyl,            —C(═O)OR^(8a), —S(═O)₂R^(8a), —C(═O)R^(8b), or            —C(═O)NR^(8b)R^(8c);        -   R⁶ is H, alkyl, cycloalkyl, alkylcycloalkyl, or aralkyl;        -   R⁷ is H, alkyl, aralkyl, or aryl;        -   R^(8a) is alkyl, cycloalkyl, cycloalkylalkyl, heteroaryl,            heteroarylalkyl, aralkyl, or aryl;        -   R^(8b) and R^(8c) are each independently H, alkyl,            cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl,            aralkyl, or aryl; or R^(8b) and R^(8c) taken together with            the nitrogen atom to which they are connected form a 4- to            8-membered heterocycloalkyl ring;        -   m is 1 or 2; and        -   n is 0, 1, or 2;        -   with the provisos that:            -   at least one of m and n is other than 2; and            -   when X is NR⁵, then n is 1 or 2;        -   or a pharmaceutically acceptable salt thereof.

In yet another embodiment, the invention is directed to methods oftreating pain, comprising the step of administering to a patient in needthereof, a composition, comprising an effective amount of an opioid, andan effective amount of a compound of the invention, preferably acompound of formula Ia:

-   -   wherein:        -   R¹ is —OH, —CH₂OH, —C(═O)OR⁶, —C(═O)NR⁶R⁷, or —NR⁶R⁷;        -   R² and R³ are each independently alkyl or alkenyl;        -   R⁴ is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl,            heteroaryl, aralkyl, alkylaralkyl, or heteroarylalkyl;        -   X is CH₂ or NR⁵;        -   R⁵ is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl,            heteroaryl, aralkyl, alkylaralkyl, heteroarylalkyl,            —C(═O)OR^(8a), —S(═O)₂R^(8a), —C(═O)R^(8b), or            —C(═O)NR^(8b)R^(8c);        -   R⁶ is H, alkyl, cycloalkyl, alkylcycloalkyl, or aralkyl;        -   R⁷ is H, alkyl, aralkyl, or aryl;        -   R^(8a) is alkyl, cycloalkyl, cycloalkylalkyl, heteroaryl,            heteroarylalkyl, aralkyl, or aryl;        -   R^(8b) and R^(8c) are each independently H, alkyl,            cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl,            aralkyl, or aryl; or R^(8b) and R^(8c) taken together with            the nitrogen atom to which they are connected form a 4- to            8-membered heterocycloalkyl ring;        -   m is 1 or 2; and        -   n is 0, 1, or 2;        -   with the provisos that:            -   at least one of m and n is other than 2; and            -   when X is NR⁵, then n is 1 or 2;        -   or a pharmaceutically acceptable salt thereof.

In yet another embodiment, the invention is directed to methods forbinding opioid receptors, in a patient in need thereof, comprising thestep of administering to the patient a composition comprising aneffective amount of a compound of the invention, preferably a compoundof formula IIIa:

-   -   wherein:        -   R¹ is —OH, —CH₂OH, —C(═O)OR⁶, —C(═O)NR⁶R⁷, or —NR⁶R⁷;        -   R² and R³ are each independently alkyl or alkenyl;        -   R⁴ is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl,            heteroaryl, aralkyl, alkylaralkyl, or heteroarylalkyl;        -   X is CH₂ or NR⁵;        -   R⁵ is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl,            heteroaryl, aralkyl, alkylaralkyl, heteroarylalkyl,            heterocycloalkylalkyl, —C(═O)OR^(8a), —S(═O)₂R^(8a),            —C(═O)R^(8b), or —C(═O)NR^(8b)R^(8c);        -   R⁶ is H, alkyl, cycloalkyl, alkylcycloalkyl, or aralkyl;        -   R⁷ is H, alkyl, aralkyl, or aryl;        -   R^(8a) is alkyl, cycloalkyl, cycloalkylalkyl, heteroaryl,            heteroarylalkyl, aralkyl, or aryl;        -   R^(8b) and R^(8c) are each independently H, alkyl,            cycloalkyl, cycloalkylalkyl, heteroaryl, heterocycloalkyl,            heterocycloalkylalkyl, heteroarylalkyl, aralkyl, or aryl; or            R^(8b) and R^(8c) taken together with the nitrogen atom to            which they are connected form a 4- to 8-membered            heterocycloalkyl ring;        -   m is 1 or 2; and        -   n is 0, 1, or 2;        -   with the provisos that:            -   at least one of m and n is other than 2; and            -   when X is NR⁵, then n is 1 or 2;        -   or a pharmaceutically acceptable salt thereof.

In other embodiments, the invention is directed to methods of treatinggastrointestinal dysfunction, comprising the step of administering to apatient in need thereof, a composition comprising an effective amount ofa compound of the invention, preferably a compound of formula IIIa.

In yet other embodiments, the invention is directed to methods oftreating ileus, comprising the step of administering to a patient inneed thereof, a composition comprising an effective amount of a compoundof the invention, preferably a compound of formula IIIa.

In still other embodiments, the invention is directed to methods oftreating obesity, comprising the step of administering to a patient inneed thereof, a composition comprising an effective amount of a compoundof the invention, preferably a compound of formula IIIa.

In another embodiment, the invention is directed to methods of treatinga side effect associated with an opioid, comprising the step ofadministering to a patient in need thereof, a composition comprising aneffective amount of a compound of the invention, preferably a compoundof formula IIIa.

In yet another embodiment, the invention is directed to methods oftreating pain, comprising the step of administering to a patient in needthereof, a composition, comprising an effective amount of an opioid; andan effective amount of a compound of the invention, preferably acompound of formula IIIa.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

The present invention is generally directed to quinolizidine andoctahydro-pyridopyrazine compounds, pharmaceutical compositionscontaining these compounds, and methods of their pharmaceutical use.

As employed above and throughout the disclosure, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings.

As used herein, the term “alkyl” refers to an optionally substituted,saturated, straight or branched hydrocarbon having from about 1 to about20 carbon atoms (and all combinations and subcombinations of ranges andspecific numbers of carbon atoms therein), with from about 1 to about 8carbon atoms, herein referred to as “lower alkyl,” being preferred.Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl,neopentyl, n-hexyl, isohexyl, 3-methylpentyl, 2,2-dimethylbutyl, and2,3-dimethylbutyl.

As used herein, the term “cycloalkyl” refers to an optionallysubstituted alkyl group having one or more rings in their structures andhaving from about 3 to about 20 carbon atoms (and all combinations andsubcombinations of ranges and specific numbers of carbon atoms therein),with from about 3 to about 10 carbon atoms being preferred. Multi-ringstructures may be bridged or fused ring structures. Groups include, butare not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cyclooctyl, 2-[4-isopropyl-1-methyl-7-oxa-bicyclo[2.2.1]heptanyl],2-[1,2,3,4-tetrahydro-naphthalenyl], and adamantyl.

As used herein, the term “cycloalkylalkyl” refers to an optionallysubstituted ring system comprising an alkyl radical bearing a cycloalkylsubstituent, and having from about 6 to about 50 carbon atoms (and allcombinations and subcombinations of ranges and specific numbers ofcarbon atoms therein), with from about 6 to about 10 carbon atoms beingpreferred, wherein alkyl and cycloalkyl are as previously defined.Non-limiting examples include, for example, cyclopropylmethyl,cyclobutylethyl, cyclopentylpropyl, cyclohexylmethyl,2-cyclooctyl-1-methylethyl,2-[4-isopropyl-1-methyl-7-oxa-bicyclo[2.2.1]heptanyl]methyl,2-[1,2,3,4-tetrahydro-naphthalenyl]ethyl, and adamantylpropyl.

As used herein, the term “alkylcycloalkyl” refers to an optionallysubstituted ring system comprising a cycloalkyl group having one or morealkyl substituents, wherein cycloalkyl and alkyl are each as previouslydefined. Exemplary alkylcycloalkyl groups include 2-methylcyclohexyl,3,3-dimethylcyclopentyl, trans-2,3-dimethylcyclooctyl, and4-methyldecahydronaphthalenyl.

As used herein, the term “heterocycloalkyl” refers to an optionallysubstituted, mono-, di-, tri-, or other multicyclic aliphatic ringsystem that includes at least one, and preferably from 1 to about 4sulfur, oxygen, or nitrogen heteroatom ring members. Heterocycloalkylgroups can have from about 3 to about 20 carbon atoms (and allcombinations and subcombinations of ranges and specific numbers ofcarbon atoms therein), with from about 4 to about 10 carbons beingpreferred. In more preferred embodiments, the heterocycloalkyl groupshave from about 4 to about 8 ring members, wherein 1 or 2 members aresulfur, oxygen, or nitrogen and the remaining members are carbon atoms.The heterocycloalkyl group may be unsaturated, and may also be fused toaromatic rings. Examples of heterocycloalkyl groups include, forexample, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl,pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl,oxazolidinyl, thiazolidinyl, piperazinyl, morpholinyl, piperadinyl,decahydroquinolyl, octahydrochromenyl, octahydro-cyclopenta[c]pyranyl,1,2,3,4,-tetrahydroquinolyl, octahydro-[2]pyridinyl,decahydro-cycloocta[c]furanyl, and imidazolidinyl.

As used herein, the term “alkenyl” refers to an optionally substitutedalkyl group having from about 2 to about 10 carbon atoms and one or moredouble bonds (and all combinations and subcombinations of ranges andspecific numbers of carbon atoms therein), wherein alkyl is aspreviously defined.

As used herein, the term “alkynyl” refers to an optionally substitutedalkyl group having from about 2 to about 10 carbon atoms and one or moretriple bonds (and all combinations and subcombinations of ranges andspecific numbers of carbon atoms therein), wherein alkyl is aspreviously defined.

As used herein, the term “aryl” refers to an optionally substituted,mono-, di-, tri-, or other multicyclic aromatic ring system having fromabout 5 to about 50 carbon atoms (and all combinations andsubcombinations of ranges and specific numbers of carbon atoms therein),with from about 6 to about 10 carbons being preferred. Non-limitingexamples include, for example, phenyl, naphthyl, anthracenyl, andphenanthrenyl.

As used herein, the term “aralkyl” refers to an optionally substitutedring system comprising an alkyl radical bearing an aryl substituent andhaving from about 6 to about 50 carbon atoms (and all combinations andsubcombinations of ranges and specific numbers of carbon atoms therein),with from about 6 to about 10 carbon atoms being preferred. Non-limitingexamples include, for example, benzyl, diphenylmethyl, triphenylmethyl,phenylethyl, and diphenylethyl.

As used herein, the term “alkylaralkyl” refers to an optionallysubstituted ring system comprising an alkyl radical bearing an aralkylsubstituent and having from about 6 to about 50 carbon atoms (and allcombinations and subcombinations of ranges and specific numbers ofcarbon atoms therein), with from about 6 to about 10 carbon atoms beingpreferred, wherein alkyl and aralkyl are as previously defined.Non-limiting examples include, for example, tolylmethyl,bis(isopropylphenyl)methyl, 1-tolyl-1-ethylphenylmethyl,tert-butylphenylethyl, and ortho-methyl-para-butylphenylethyl.

As used herein, the term “alkoxyl” refers to an optionally substitutedalkyl-O— group wherein alkyl is as previously defined. In some preferredembodiments, the alkyl moieties of the alkoxy groups have from about 1to about 4 carbon atoms. Exemplary alkoxy groups include, but are notlimited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, andheptoxy.

As used herein, the term “aryloxyl” refers to an optionally substitutedaryl-O— group wherein aryl is as previously defined. Exemplary aryloxygroups include, but are not limited to, phenoxyl and naphthoxyl.

As used herein, the term “aralkoxyl” refers to an optionally substitutedaralkyl-O— group wherein aralkyl is as previously defined. Exemplaryaralkoxy groups include, but are not limited to, benzyloxy,1-phenylethoxy, 2-phenylethoxy, and 3-naphthylheptoxy.

As used herein, the term “halo” refers to a fluoro, chloro, bromo, oriodo moiety attached to a compound of the invention.

As used herein, the term “heteroaryl” refers to an optionallysubstituted, mono-, di-, tri- or other multicyclic aromatic ring systemthat includes at least one, and preferably from 1 to about 4 sulfur,oxygen, or nitrogen heteroatom ring members. Heteroaryl groups can have,for example, from about 3 to about 50 carbon atoms (and all combinationsand subcombinations of ranges and specific numbers of carbon atomstherein), with from about 4 to about 10 carbons being preferred.Non-limiting examples of heteroaryl groups include, for example, pyrryl,furyl, pyridyl, 1,2,4-thiadiazolyl, pyrimidyl, thienyl, isothiazolyl,imidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl,thiophenyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, purinyl,carbazolyl, benzimidazolyl, and isoxazolyl. Heteroaryl may be optionallyattached via a carbon or a heteroatom to the rest of the molecule.

As used herein, the term “heteroarylalkyl” refers to an optionallysubstituted ring system comprising an alkyl radical bearing a heteroarylsubstituent, having from about 2 to about 50 carbon atoms (and allcombinations and subcombinations of ranges and specific numbers ofcarbon atoms therein), with from about 6 to about 25 carbon atoms beingpreferred. Non-limiting examples include 2-(1H-pyrrol-3-yl)ethyl,3-pyridylmethyl, 5-(2H-tetrazolyl)methyl, and3-(pyrimidin-2-yl)-2-methylcyclopentanyl.

As used herein, the term “spiroalkyl” refers to an optionallysubstituted alkylene diradical, both ends of which are bonded to thesame carbon atom of the parent group to form a spirocyclic group. Thespirocyclic group, as herein defined, has 3 to 20 ring atoms, preferablywith 3 to 10 ring atoms. Exemplary spiroalkyl groups taken together withits parent group include, but are not limited to,1-(1-methyl-cyclopropyl)-propan-2-one,2-(1-phenoxy-cyclopropyl)-ethylamine, and 1-methyl-spiro[4.7]dodecane.

Typically, substituted chemical moieties include one or moresubstituents that replace hydrogen. Exemplary substituents include, forexample, halo (e.g., F, Cl, Br, I), alkyl, cycloalkyl, alkylcycloalkyl,alkenyl, alkynyl, aralkyl, aryl, heteroaryl, heteroarylalkyl,spiroalkyl, heterocycloalkyl, hydroxyl (—OH), alkoxyl, aryloxyl,aralkoxyl, nitro (—NO₂), cyano (—CN), amino (—NH₂), N-substituted amino(—NHR″), N,N-disubstituted amino (—N(R″)R″), carboxyl (—COOH), —C(═O)R″,—OR″, —C(═O)OR″, —C(═O)NHSO₂R″, —NHC(═O)R″, aminocarbonyl (—C(═O)NH₂),N-substituted aminocarbonyl (—C(═O)NHR″), N,N-disubstitutedaminocarbonyl (—C(═O)N(R″)R″), thiolato (SR″), sulfonic acid and itsesters (—SO₃R″), phosphonic acid and its mono-ester (—P(═O)(OR″)(OH) anddi-esters (—P(═O)(OR″)(OR″), —S(═O)₂R″, —S(═O)₂NH₂, —S(═O)₂NHR″,—S(═O)₂NR″R″, —SO₂NHC(═O)R″, —NHS(═O)₂R″, —NR″S(═O)₂R″, —CF₃, —CF₂CF₃,—NHC(═O)NHR″, —NHC(═O)NR″R″, —NR″C(═O)NHR″, —NR″C(═O)NR″R″, —NR″C(═O)R″and the like. Aryl substituents may also include(CH₂)_(u)SO₂NR″(CH₂)_(v) and (CH₂)_(u)CO₂NR″(CH₂)_(v), where u and vare, independently, 0 to 3, where the methylene units are attached in a1,2 arrangement yielding substituted aryls of the type:

In relation to the aforementioned substituents, each moiety R″ can be,independently, any of H, alkyl, cycloalkyl, alkenyl, aryl, aralkyl,heteroaryl, or heterocycloalkyl, or when (R″(R″)) is attached to anitrogen atom, R″ and R″ can be taken together with the nitrogen atom towhich they are attached to form a 4- to 8-membered nitrogen heterocycle,wherein the heterocycloalkyl ring is optionally interrupted by one ormore additional —O—, —S—, —SO, —SO₂—, —NH—, —N(alkyl)-, or —N(aryl)-groups, for example.

As used herein, the term “antagonist” refers to a compound that binds toa receptor to form a complex that preferably does not elicit anyresponse, in the same manner as an unoccupied receptor, and does notalter the equilibrium between inactive and active receptor.

As used herein, the term “prodrug” refers to compounds that may serve tomaximize the amount of active species that reaches the desired site ofreaction that are themselves typically inactive or minimally active forthe activity desired, but through biotransformation are converted intobiologically active metabolites.

As used herein, the term “stereoisomers” refers to compounds that haveidentical chemical constitution, but differ as regards the arrangementof the atoms or groups in space.

As used herein, the term “partial stereoisomers” refers to stereoisomershaving two or more chiral centers wherein at least one of the chiralcenters has defined stereochemistry (i.e., R or S) and at least one hasundefined stereochemistry (i.e., R or S). When the term “partialstereoisomers thereof” is used herein, it refers to any compound withinthe described genus whose configuration at chiral centers with definedstereochemistry centers is maintained and the configuration of eachundefined chiral center is independently selected from R or S. Forexample, if a stereoisomer has three chiral centers and thestereochemical configuration of the first center is defined as having“S” stereochemistry, the term “or partial stereoisomer thereof” refersto stereoisomers having SRR, SRS, SSR, or SSS configurations at thethree chiral centers, and mixtures thereof.

As used herein, the term “optically enriched” denotes the presence ofone or more non-racemic stereoisomeric centers in a molecule, whereinthe configuration of at least one stereoisomeric center has apredominance of one stereoisomeric configuration (R or S). For example,one stereoisomeric center in a molecule, typically a carbon atom, mayhave greater than 50% of its attached atoms spatially arranged in the(R) configuration. Alternatively, more than 50% may be spatiallyarranged in the (S) configuration. A predominance of one stereoisomericconfiguration (R or S) occurring at one or more centers in a givenmolecule is considered non-racemic within the definition hereinprovided. For example, if a compound has three stereoisomeric centersand at least one of the stereoisomeric centers has greater than 50% ofits attached atoms spatially arranged in the (R) configuration (or the(S) configuration), the molecule is non-racemic. In compounds havingmore than one stereoisomeric center, all stereoisomers possible from anycombination of (R) or (S) stereoisomeric center configurations,including those combinations that are optically pure at eachstereoisomeric center are within the ambit of the term “non-racemicstereoisomer”, so long as at least one stereoisomeric center has greaterthan 50% of its attached atoms spatially arranged in either the (R)configuration or the (S) configuration. More preferably the molecule, orits stereoisomeric center, is substantially optically enriched, and evenmore preferably is substantially enantiomerically pure.

As used herein, the term “substantially optically enriched”, whenreferring to a stereoisomer or stereoisomeric center, denotes that atleast about 60%, preferably about 70%, more preferably about 80%, stillmore preferably about 90% of one stereoisomer or one stereoisomericcenter configuration predominates in the mixture, with at least about95% of one stereoisomer or one stereoisomeric center configuration beingeven more preferred. In some preferred embodiments, the compound is“substantially enantiomerically pure”, that is, at least about 97.5%,more preferably about 99%, even more preferably about 99.5% of onestereoisomeric configuration predominates.

In some compounds, several stereoisomeric centers may be present. Thepresence of multiple stereoisomeric centers in a single structureindicates that multiple (R)/(S) racemic pairs of stereoisomers may bepresent, but that each pair of stereoisomers is diastereomeric relativeto the other pair. As such, the first pair of enantiomers having, forexample, two chiral centers may have the configurations, for example,(R, R) and (S,S). The second pair then have configurations, for example,(R, S) and (S,R).

As used herein, the term “N-oxide” refers to compounds wherein the basicnitrogen atom of either a heteroaromatic ring or tertiary amine isoxidized to give a quaternary nitrogen bearing a positive formal chargeand an attached oxygen atom bearing a negative formal charge.

As used herein, the term “pharmaceutically acceptable salts” refer toderivatives of the disclosed compounds wherein the parent compound ismodified by making acid or base salts thereof. Examples ofpharmaceutically acceptable salts include, but are not limited to,mineral or organic acid salts of basic residues such as amines; alkalior organic salts of acidic residues such as carboxylic acids; and thelike. The pharmaceutically acceptable salts include the conventionalnon-toxic salts or the quaternary ammonium salts of the parent compoundformed, for example, from non-toxic inorganic or organic acids. Forexample, such conventional non-toxic salts include those derived frominorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic,phosphoric, nitric, and the like; and the salts prepared from organicacids such as acetic, propionic, succinic, glycolic, stearic, lactic,malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic,phenylacetic, glutamic, benzoic, salicylic, sulfanilic,2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, and the like. These physiologicallyacceptable salts are prepared by methods known in the art, e.g., bydissolving the free amine bases with an excess of the acid in aqueousalcohol, or neutralizing a free carboxylic acid with an alkali metalbase such as a hydroxide, or with an amine.

Compounds described herein throughout may exist in alternate forms andsuch alternate forms are intended to be included within the scope of thecompounds described and claimed in the present application. Accordingly,reference herein to compounds of formula I is intended to includereference to these alternate forms. For example, many amino-containingcompounds can be used or prepared as an acid addition salt. Often suchsalts improve isolation and handling properties of the compound. Forexample, depending on the reagents, reaction conditions, and the like,compounds as described herein can be used or prepared, for example, astheir hydrochloride or tosylate salts. Alternate forms of the compoundsdescribed herein also include, for example, isomorphic crystallineforms, all chiral and racemic forms, including stereoisomeric andpartial stereoisomeric forms, N-oxides, hydrates, solvates, and acidsalt hydrates.

Certain acidic or basic compounds of the present invention may exist aszwitterions. All forms of the compounds, including free acid, free base,and zwitterions, are contemplated to be within the scope of the presentinvention. It is well known in the art that compounds containing bothbasic nitrogen atom and acidic groups often exist in equilibrium withtheir zwitterionic forms. Thus, any of the compounds described hereinthroughout that contain, for example, both basic nitrogen and acidicgroups, also include reference to their corresponding zwitterions.

As used herein, the term “effective amount” refers to an amount of acompound as described herein that may be therapeutically effective toinhibit, prevent, or treat the symptoms of particular disease, disorder,or side effect. Such diseases, disorders, and side effects include, butare not limited to, those pathological conditions associated with theadministration of opioids (for example, in connection with the treatmentand/or prevention of pain), wherein the treatment or preventioncomprises, for example, inhibiting the activity thereof by contactingcells, tissues, or receptors with compounds of the present invention.Thus, for example, the term “effective amount,” when used in connectionwith opioids, for example, for the treatment of pain, refers to thetreatment and/or prevention of the painful condition. The term“effective amount,” when used in connection with opioid antagonistcompounds, refers to the treatment and/or prevention of side effectstypically associated with opioids including, for example, such sideeffects as constipation, nausea, and/or vomiting, as well as other sideeffects, discussed in further detail below. The term “effective amount,”when used in connection with compounds active against gastrointestinaldysfunction, refers to the treatment and/or prevention of symptoms,diseases, disorders, and conditions typically associated withgastrointestinal dysfunction. The term “effective amount,” when used inconnection with anti-ileus compounds, refers to the treatment and/orprevention of symptoms, diseases, disorders, and conditions typicallyassociated with ileus. The term “effective amount,” when used inconnection with compounds effective against obesity, refers to thetreatment and/or prevention of the obese condition.

As used herein, the term “pharmaceutically acceptable” refers to thosecompounds, materials, compositions, and/or dosage forms that are, withinthe scope of sound medical judgment, suitable for contact with thetissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problems or complicationscommensurate with a reasonable benefit/risk ratio. The term specificallyencompasses veterinary uses.

As used herein, the expressions “in combination with,” “combinationtherapy,” and “combination products” refer, in certain embodiments, tothe concurrent administration to a patient of opioids, an anestheticagent (inhaled anesthetic, hypnotic, anxiolytic, neuromuscular blockerand opioid) and/or optional ingredients (antibiotics, antivirals,antifungals, anti-inflammatories, anesthetics, and mixtures thereof) andthe compounds of the invention, preferably compounds of formula Ia. Whenadministered in combination, each component may be administered at thesame time or sequentially in any order at different points in time.Thus, each component may be administered separately but sufficientlyclosely in time so as to provide the desired therapeutic effect.

As used herein, the term “dosage unit” refers to physically discreteunits suited as unitary dosages for the particular individual to betreated. Each unit may contain a predetermined quantity of activecompound(s) calculated to produce the desired therapeutic effect(s) inassociation with the required pharmaceutical carrier. The specificationfor the dosage unit forms of the invention may be dictated by (a) theunique characteristics of the active compound(s) and the particulartherapeutic effect(s) to be achieved, and (b) the limitations inherentin the art of compounding such active compound(s).

The term “treatment” as used herein includes preventative (e.g.,prophylactic), curative or palliative treatment and “treating” as usedherein also includes preventative, curative and palliative treatment.

As used herein, the term “pain” refers to the perception or condition ofunpleasant sensory or emotional experience, associated with actual orpotential tissue damage or described in terms of such damage. “Pain”includes, but is not limited to, two broad categories of pain: acute andchronic pain (Buschmann, H.; Christoph, T; Friderichs, E.; Maul, C.;Sundermann, B; eds.; Analgesics, Wiley-VCH, Verlag GMbH & Co. KgaA,Weinheim; 2002; Jain, K. K. “A Guide to Drug Evaluation for ChronicPain”; Emerging Drugs, 5(2), 241-257 (2000)). Non-limiting examples ofpain include nociceptive pain, inflammatory pain, visceral pain, somaticpain, neuropathic pain, AIDS pain, cancer pain, phantom pain, andpsychogenic pain, and pain resulting from hyperalgesia, pain caused byrheumatoid arthritis, migraine, allodynia, and the like.

As used herein, the term “gastrointestinal dysfunction” referscollectively to maladies of the stomach, and small and large intestines.Non-limiting examples of gastrointestinal dysfunction include, forexample, diarrhea, nausea, emesis, post-operative emesis, opioid-inducedemesis, irritable bowel syndrome, opioid-bowel dysfunction, opioidinduced constipation, post-operative ileus, opioid-induced ileus,colitis, decreased gastric motility, decreased gastric emptying,inhibition of small intestinal propulsion, inhibition of largeintestinal propulsion, increased amplitude of non-propulsive segmentalcontractions, constriction of sphincter of Oddi, increased analsphincter tone, impaired reflex relaxation with rectal distention,diminished gastric, biliary, pancreatic or intestinal secretions,increased absorption of water from bowel contents, gastro-esophagealreflux, gastroparesis, cramping, bloating, distension, abdominal orepigastric pain and discomfort, non-ulcerogenic dyspepsia, gastritis,constipation, or delayed absorption of orally administered medicationsor nutritive substances.

As used herein, the term “ileus” refers to the obstruction of the bowelor gut, especially the colon. See, e.g., Dorland's Illustrated MedicalDictionary, p. 816, 27th ed. (W.B. Saunders Company, Philadelphia 1988).Ileus should be distinguished from constipation, which refers toinfrequent or difficulty in evacuating the feces. See, e.g., Dorland'sIllustrated Medical Dictionary, p. 375, 27th ed. (W.B. Saunders Company,Philadelphia 1988). Ileus may be diagnosed by the disruption of normalcoordinated movements of the gut, resulting in failure of the propulsionof intestinal contents. See, e.g., Resnick, J. Am. J. ofGastroenterology 1997, 92, 751 and Resnick, J., Am. J. ofGastroenterology, 1997, 92, 934. In some instances, particularlyfollowing surgery, including surgery of the abdomen, the boweldysfunction may become quite severe, lasting for more than a week andaffecting more than one portion of the GI tract. This condition is oftenreferred to as post-surgical (or post-operative) paralytic ileus andmost frequently occurs after laparotomy (see Livingston, E. H. andPassaro, E. D. Jr. Digestive Diseases and Sciences 1990, 35, 121).Similarly, post-partum ileus is a common problem for women in the periodfollowing childbirth, and is thought to be caused by similarfluctuations in natural opioid levels as a result of birthing stress.

As used herein, the term “patient” refers to animals, including mammals,preferably humans.

As used herein, the term “side effect” refers to a consequence otherthan the one(s) for which an agent or measure is used, as the adverseeffects produced by a drug, especially on a tissue or organ system otherthan the one sought to be benefited by its administration. In the case,for example, of opioids, the term “side effect” may refer to suchconditions as, for example, constipation, nausea, and/or vomiting.

When any variable occurs more than one time in any constituent or in anyformula, its definition in each occurrence is independent of itsdefinition at every other occurrence. Combinations of substituentsand/or variables are permissible only if such combinations result instable compounds.

It is believed the chemical formulas and names used herein correctly andaccurately reflect the underlying chemical compounds. However, thenature and value of the present invention does not depend upon thetheoretical correctness of these formulae, in whole or in part. Thus itis understood that the formulas used herein, as well as the chemicalnames attributed to the correspondingly indicated compounds, are notintended to limit the invention in any way, including restricting it toany specific tautomeric form or to any specific optical or geometricisomer, except where such stereochemistry is clearly defined.

In certain preferred embodiments, the compounds, pharmaceuticalcompositions and methods of the present invention may involve an opioidantagonist compound. The term “peripheral” designates that the compoundacts primarily on physiological systems and components external to thecentral nervous system. In preferred form, the opioid antagonistcompounds employed in the methods of the present invention exhibit highlevels of activity with respect to peripheral tissue, such as,gastrointestinal tissue, while exhibiting reduced, and preferablysubstantially no, CNS activity. The phrase “substantially no CNSactivity,” as used herein, means that less than about 50% of thepharmacological activity of the compounds employed in the presentmethods is exhibited in the CNS, preferably less than about 25%, morepreferably less than about 10%, even more preferably less than about 5%and most preferably 0% of the pharmacological activity of the compoundsemployed in the present methods is exhibited in the CNS.

Furthermore, it is preferred in certain embodiments of the inventionthat the opioid antagonist compound does not substantially cross theblood-brain barrier. The phrase “does not substantially cross,” as usedherein, means that less than about 20% by weight of the compoundemployed in the present methods crosses the blood-brain barrier,preferably less than about 15% by weight, more preferably less thanabout 10% by weight, even more preferably less than about 5% by weightand most preferably 0% by weight of the compound crosses the blood-brainbarrier. Selected compounds can be evaluated for CNS penetration bydetermining plasma and brain levels following i.v. administration.

Accordingly, in one embodiment, the present invention provides compoundsof formula I:

-   -   wherein:        -   R¹ is —OH, —OR^(a), —CH₂OH, —C(═O)OR⁶, —C(═O)NR⁶R⁷, or            —NR⁶R⁷;        -   R² and R³ are each independently alkyl or alkenyl;        -   R⁴ is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl,            heteroaryl, aralkyl, alkylaralkyl, or heteroarylalkyl;        -   X is CH₂ or NR⁵;        -   R⁵ is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl,            heteroaryl, aralkyl, alkylaralkyl, heteroarylalkyl,            —C(═O)OR^(8a), —S(═O)₂R^(8a), —C(═O)R^(8b), or            —C(═O)NR^(8b)R^(8c);        -   R⁶ is H, alkyl, cycloalkyl, alkylcycloalkyl, or aralkyl;        -   R⁷ is H, alkyl, aralkyl, or aryl;        -   R^(8a) is alkyl, cycloalkyl, cycloalkylalkyl, heteroaryl,            heteroarylalkyl, aralkyl, or aryl;        -   R^(8b) and R^(8c) are each independently H, alkyl,            cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl,            aralkyl, or aryl; or R^(8b) and R^(8c) taken together with            the nitrogen atom to which they are connected form a 4- to            8-membered heterocycloalkyl ring;        -   R^(a) is a hydroxyl protecting group;        -   m is 1 or 2; and        -   n is 0, 1, or 2;        -   with the provisos that:            -   at least one of m and n is other than 2; and            -   when X is NR⁵, then n is 1 or 2;        -   or a pharmaceutically acceptable salt thereof.

In certain preferred embodiments, the compounds of formula I have thestructure Ia:

-   -   wherein:        -   R¹ is —OH, —CH₂OH, —C(═O)OR⁶, —C(═O)NR⁶R⁷, or —NR⁶R⁷;        -   R² and R³ are each independently alkyl or alkenyl;        -   R⁴ is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl,            heteroaryl, aralkyl, alkylaralkyl, or heteroarylalkyl;        -   X is CH₂ or NR⁵;        -   R⁵ is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl,            heteroaryl, aralkyl, alkylaralkyl, heteroarylalkyl,            —C(═O)OR^(8a), —S(═O)₂R^(8a), —C(═O)R^(8b), or            —C(═O)NR^(8b)R^(8c);        -   R⁶ is H, alkyl, cycloalkyl, alkylcycloalkyl, or aralkyl;        -   R⁷ is H, alkyl, aralkyl, or aryl;        -   R^(8a) is alkyl, cycloalkyl, cycloalkylalkyl, heteroaryl,            heteroarylalkyl, aralkyl, or aryl;        -   R^(8b) and R^(8c) are each independently H, alkyl,            cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl,            aralkyl, or aryl; or R^(8b) and R^(8c) taken together with            the nitrogen atom to which they are connected form a 4- to            8-membered heterocycloalkyl ring;        -   m is 1 or 2; and        -   n is 0, 1, or 2;        -   with the provisos that:            -   at least one of m and n is other than 2; and            -   when X is NR⁵, then n is 1 or 2;        -   or a pharmaceutically acceptable salt thereof.

More preferably when compounds of formula I have the structure Ia, R¹ is—OH, —C(═O)OR⁶, —C(═O)NR⁶R⁷, or —NR⁶R⁷, yet more preferably —OH,—C(═O)NR⁶R⁷, or —NR⁶R⁷, still more preferably —OH or —C(═O)NR⁶R⁷.

In certain preferred embodiments of compounds of formula I, R² and R³are each independently C₁-C₆alkyl or C₂-C₆alkenyl, more preferablyC₁-C₃alkyl or C₂-C₃alkenyl, more preferably still C₁-C₃alkyl, yet morepreferably C₁alkyl, still more preferably methyl.

In certain preferred embodiments of compounds of formula I, R⁴ is H,alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, aralkyl,alkylaralkyl, or heteroarylalkyl, with H, alkyl, cycloalkyl, aryl, oraralkyl being more preferred. When R⁴ is alkyl, it is preferablyC₁-C₆alkyl, more preferably C₁-C₃alkyl, yet more preferably C₁alkyl,still more preferably methyl. When R⁴ is cycloalkyl, it is preferablyC₃-C₁₀cycloalkyl, more preferably C₃-C₈cycloalkyl, yet more preferablyC₃-C₆cycloalkyl, still more preferably C₅-C₆cycloalkyl, still morepreferably optionally substituted cyclopentyl or optionally substitutedcyclohexyl. When R⁴ is cycloalkylalkyl, it is preferablyC₃-C₁₀cycloalkylC₁-C₆alkyl, more preferably C₃-C₈cycloalkylC₁-C₃alkyl,yet more preferably C₃-C₆cycloalkylC₁-C₃alkyl, still more preferablyC₅-C₆cycloalkylC₁-C₃alkyl, still more preferably cyclopentylC₁-C₃alkylor cyclohexylC₁-C₃alkyl, yet more preferably cyclopentylC₁alkyl orcyclohexylC₁alkyl, even more preferably optionally substitutedcyclopentylmethyl or optionally substituted cyclohexylmethyl. When R⁴ isaryl, it is preferably C₆-C₁₀aryl, more preferably C₆aryl, yet morepreferably phenyl. When R⁴ is heteroaryl, it is preferablyC₅-C₁₀heteroaryl, more preferably C₅-C₆heteroaryl, still more preferablypyridinyl or thienyl. When R⁴ is aralkyl, it is preferablyC₆-C₁₀arylC₁-C₆alkyl, more preferably C₆-C₁₀arylC₁-C₃alkyl, yet morepreferably C₆arylC₁-C₃alkyl, still more preferably C₆arylC₁alkyl, yetmore preferably optionally substituted benzyl. When R⁴ is alkylaralkyl,it is preferably C₁-C₆alkylC₆-C₁₀arylC₁-C₆alkyl, more preferablyC₁-C₄alkylC₆-C₁₀arylC₁-C₃alkyl, yet more preferablyC₁-C₄alkylC₆arylC₁-C₃alkyl, still more preferably C₁alkylC₆arylC₁alkyl,yet more preferably optionally substituted methylbenzyl. When R⁴ isheteroarylalkyl, it is preferably C₅-C₁₀heteroarylC₁-C₆alkyl, morepreferably C₅-C₁₀heteroarylC₁-C₃alkyl, yet more preferablyC₅-C₆heteroarylC₁-C₃alkyl, still more preferably C₅-C₆heteroarylC₁alkyl.In certain preferred embodiments, R⁴ is H.

In certain preferred embodiments of compounds of formula I, X is NR⁵.

In certain preferred embodiments of compounds of formula I, R⁵ is H,alkyl, aryl, cycloalkylalkyl, aralkyl, alkylaralkyl, heteroarylalkyl,—S(═O)₂R^(8a), —C(═O)R^(8b), or —C(═O)NR^(8b)R^(8c), more preferably—C(═O)R^(8b) or —S(═O)₂R^(8a), still more preferably —C(═O)R^(8b). Inother preferred embodiments, R⁵ is H, alkyl, aryl, cycloalkylalkyl,aralkyl, alkylaralkyl, heteroarylalkyl. When R⁵ is alkyl, it ispreferably C₁-C₆alkyl, more preferably C₁-C₃alkyl, yet more preferablyC₁alkyl, still more preferably methyl optionally substituted withcarboxy. When R⁵ is cycloalkyl, it is preferably C₃-C₁₀cycloalkyl, morepreferably C₃-C₈cycloalkyl, yet more preferably C₃-C₆cycloalkyl, stillmore preferably C₅-C₆cycloalkyl, still more preferably optionallysubstituted cyclopentyl or optionally substituted cyclohexyl. When R⁵ iscycloalkylalkyl, it is preferably C₃-C₁₀cycloalkylC₁-C₆alkyl, morepreferably C₃-C₈cycloalkylC₁-C₃alkyl, yet more preferablyC₃-C₆cycloalkylC₁-C₃alkyl, still more preferablyC₅-C₆cycloalkylC₁-C₃alkyl, still more preferably cyclopentylC₁-C₃alkylor cyclohexylC₁-C₃alkyl, yet more preferably optionally substitutedcyclopentylmethyl or optionally substituted cyclohexylmethyl. When R⁵ isaryl, it is preferably C₆-C₁₀aryl, more preferably C₆aryl, yet morepreferably phenyl. When R⁵ is heteroaryl, it is preferablyC₅-C₁₀heteroaryl, more preferably C₅-C₆heteroaryl, even more preferablypyridinyl or pyrimidinyl. When R⁵ is aralkyl, it is preferablyC₆-C₁₀arylC₁-C₆alkyl, more preferably C₆-C₁₀arylC₁-C₃alkyl, yet morepreferably C₆arylC₁-C₃alkyl, still more preferably C₆arylC₁alkyl, yetmore preferably benzyl optionally substituted with C₁-C₆alkyl, halo,hydroxy, or heteroaryl, yet more preferably 2-chlorobenzyl,3-chlorobenzyl, 2-hydroxylbenzyl, 2-methylbenzyl, 3-methylbenzyl,2,4,5-trimethylbenzyl, or 2-(pyrid-4-yl)benzyl. When R⁵ is alkylaralkyl,it is preferably C₁-C₆alkylC₆-C₁₀arylC₁-C₆alkyl, more preferablyC₁-C₄alkylC₆-C₁₀arylC₁-C₃alkyl, yet more preferablyC₁-C₄alkylC₆arylC₁-C₃alkyl, still more preferably C₁alkylC₆arylC₁alkyl,yet more preferably optionally substituted methylbenzyl. When R⁵ isheteroarylalkyl, it is preferably C₅-C₁₀heteroarylC₁-C₆alkyl, morepreferably C₅-C₁₀heteroarylC₁-C₃alkyl, yet more preferablyC₅-C₆heteroarylC₁-C₃alkyl, still more preferably C₅-C₆heteroarylC₁alkyl,yet more preferably optionally substituted thienylmethyl. In certainpreferred embodiments, R⁵ is H.

In certain preferred embodiments of compounds of formula I, R⁶ is H,alkyl, cycloalkyl, alkylcycloalkyl, or aralkyl, with H, alkyl,alkylcycloalkyl, or aralkyl being more preferred. When R⁶ is alkyl, itis preferably C₁-C₆alkyl, more preferably C₁-C₃alkyl, yet morepreferably C₁alkyl, still more preferably methyl. When R⁶ is cycloalkyl,it is preferably C₃-C₁₀cycloalkyl, more preferably C₃-C₈cycloalkyl, yetmore preferably C₃-C₆cycloalkyl, still more preferably C₅-C₆cycloalkyl,still more preferably optionally substituted cyclopentyl or optionallysubstituted cyclohexyl. When R⁶ is alkylcycloalkyl, it is preferablyC₁-C₆alkylC₃-C₁₀cycloalkylC₁-C₆alkyl, more preferablyC₁-C₄alkylC₃-C₈cycloalkylC₁-C₃alkyl, yet more preferablyC₁-C₄alkylC₃-C₆cycloalkylC₁-C₃alkyl, still more preferablyC₁alkylC₅-C₆cycloalkylC₁alkyl, yet more preferably optionallysubstituted methylcyclopentylmethyl or optionally substitutedmethylcyclohexylmethyl. When R⁶ is aralkyl, it is preferablyC₆-C₁₀arylC₁-C₆alkyl, more preferably C₆-C₁₀arylC₁-C₃alkyl, yet morepreferably C₆arylC₁-C₃alkyl, still more preferably C₆arylC₁alkyl, yetmore preferably benzyl. In certain preferred embodiments, R⁶ is H.

In preferred embodiments of compounds of formula I, m is 1. Also inpreferred embodiments of compounds of formula I, n is 0 or 1. In certainpreferred embodiments, m and n are each 1.

In preferred embodiments of compounds of formula I, at least one of R⁴and R⁵ is H.

In certain preferred embodiments of compounds of formula I, R⁷ is H,alkyl, aralkyl, or aryl, with H being more preferred. When R⁷ is alkyl,it is preferably C₁-C₆alkyl, more preferably C₁-C₃alkyl, yet morepreferably C₁alkyl, still more preferably methyl. When R⁷ is aralkyl, itis preferably C₆-C₁₀arylC₁-C₆alkyl, more preferablyC₆-C₁₀arylC₁-C₃alkyl, yet more preferably C₆arylC₁-C₃alkyl, still morepreferably C₆arylC₁alkyl, yet more preferably benzyl. When R⁷ is aryl,it is preferably C₆-C₁₀aryl, more preferably C₆aryl, yet more preferablyphenyl.

In certain preferred embodiments of compounds of formula I, R^(8a) isalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl,aralkyl, or aryl. When R^(8a) is alkyl, it is preferably C₁-C₆alkyl,more preferably C₁-C₃alkyl, yet more preferably C₁alkyl, still morepreferably methyl. When R^(8a) is cycloalkyl, it is preferablyC₃-C₁₀cycloalkyl, more preferably C₃-C₈cycloalkyl, yet more preferablyC₃-C₆cycloalkyl, still more preferably C₅-C₆cycloalkyl, still morepreferably optionally substituted cyclopentyl or optionally substitutedcyclohexyl. When R^(8a) is cycloalkylalkyl, it is preferablyC₃-C₁₀cycloalkylC₁-C₆alkyl, more preferably C₃-C₈cycloalkylC₁-C₃alkyl,yet more preferably C₃-C₆cycloalkylC₁-C₃alkyl, still more preferablyC₅-C₆cycloalkylC₁-C₃alkyl, still more preferably cyclopentylC₁-C₃alkylor cyclohexylC₁-C₃alkyl, yet more preferably optionally substitutedcyclopentylmethyl or optionally substituted cyclohexylmethyl. WhenR^(8a) is aryl, it is preferably C₆-C₁₀aryl, more preferably C₆aryl, yetmore preferably phenyl. When R^(8a) is heteroaryl, it is preferablyC₅-C₁₀heteroaryl, more preferably C₅-C₆heteroaryl, even more preferablypyridinyl or pyrimidinyl. When R^(8a) is aralkyl, it is preferablyC₆-C₁₀arylC₁-C₆alkyl, more preferably C₆-C₁₀arylC₁-C₃alkyl, yet morepreferably C₆arylC₁-C₃alkyl, still more preferably C₆arylC₁alkyl, yetmore preferably benzyl. When R^(8a) is heteroarylalkyl, it is preferablyC₅-C₁₀heteroarylC₁-C₆ alkyl, more preferably C₅-C₁₀heteroarylC₁-C₃alkyl,yet more preferably C₅-C₆heteroarylC₁-C₃alkyl, still more preferablyC₅-C₆heteroarylC₁alkyl.

In certain preferred embodiments of compounds of formula I, R^(8b) andR^(8c) are each independently H, alkyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroarylalkyl, aralkyl, or aryl, with aryl or aralkylbeing more preferred. When R^(8b) or R^(8c) is alkyl, it is preferablyC₁-C₆alkyl, more preferably C₁-C₃alkyl, yet more preferably C₁alkyl,still more preferably methyl. When R^(8b) or R^(8c) is cycloalkyl, it ispreferably C₃-C₁₀cycloalkyl, more preferably C₃-C₈cycloalkyl, yet morepreferably C₃-C₆cycloalkyl, still more preferably C₅-C₆cycloalkyl, stillmore preferably optionally substituted cyclopentyl or optionallysubstituted cyclohexyl. When R^(8b) or R^(8c) is cycloalkylalkyl, it ispreferably C₃-C₁₀cycloalkylC₁-C₆alkyl, more preferablyC₃-C₈cycloalkylC₁-C₃alkyl, yet more preferablyC₃-C₆cycloalkylC₁-C₃alkyl, still more preferablyC₅-C₆cycloalkylC₁-C₃alkyl, still more preferably optionally substitutedcyclopentylmethyl or optionally substituted cyclohexylmethyl. WhenR^(8b) or R^(8c) is aryl, it is preferably C₆-C₁₀aryl, more preferablyC₆aryl, yet more preferably phenyl. When R^(8b) or R^(8c) is heteroaryl,it is preferably C₅-C₁₀heteroaryl, more preferably C₅-C₆heteroaryl, evenmore preferably pyridinyl. When R^(8b) or R^(8c) is aralkyl, it ispreferably C₆-C₁₀arylC₁-C₆alkyl, more preferably C₆-C₁₀arylC₁-C₃alkyl,yet more preferably C₆arylC₁-C₃alkyl, still more preferablyC₆arylC₁alkyl, yet more preferably benzyl. When R^(8b) or R^(8c) isheteroarylalkyl, it is preferably C₅-C₁₀heteroarylC₁-C₆alkyl, morepreferably C₅-C₁₀heteroarylC₁-C₃alkyl, yet more preferablyC₅-C₆heteroarylC₁-C₃alkyl, still more preferably C₅-C₆heteroarylC₁alkyl.

In certain other preferred embodiments of compounds of formula I, R^(8b)and R^(8c), taken together with the nitrogen atom to which they areconnected, form a 4- to 8-membered heterocycloalkyl ring, morepreferably a 5- to 7-membered heterocycloalkyl ring, more preferablystill, a 5- to 6-membered heterocycloalkyl ring, yet more preferably anoptionally substituted morpholine ring.

In some preferred embodiments, the compounds of formula I have thestructure corresponding to formula IIa:

In some preferred embodiments, the compounds of formula I have thestructure corresponding to formula IIb:

In particularly preferred embodiments, the compound of formula I is:

-   3-(2,3-dimethyl-7-phenyl-octahydro-1H-quinolizin-2-yl)phenol;-   1-(8-(3-hydroxyphenyl)-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)-2-phenylethanone;-   3-(7,8-dimethyl-2-phenethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   (8-(3-hydroxyphenyl)-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)    (phenyl)methanone;-   3-(2-benzyl-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(7,8-dimethyl-2-(phenylsulfonyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(7,8-dimethyl-2-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(7,8-dimethyl-3-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(2,7,8-trimethyl-3-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   2-(8-(3-hydroxyphenyl)-7,8-dimethyl-3-phenyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)acetic    acid;-   3-(8-(3-hydroxyphenyl)-7,8-dimethyl-3-phenyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)propanoic    acid;-   3-(2-benzyl-7,8-dimethyl-3-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(2-benzyl-7,8-dimethyl-3-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)benzamide;-   3-(7,8-dimethyl-3-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)benzamide;-   3-(3-benzyl-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(3-benzyl-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(3-cyclohexyl-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(2-benzyl-8,9-dimethyl-decahydropyrido[1,2-α][1,4]diazepin-9-yl)phenol;-   3-(2-(3-methoxybenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(7,8-dimethyl-2-(pyridin-2-ylmethyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(2-(cyclohexylmethyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(7,8-dimethyl-2-(4-methylbenzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(2-(2,5-dimethylbenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(7,8-dimethyl-2-(thiophen-3-ylmethyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(2-(furan-3-ylmethyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(7,8-dimethyl-2-(pyridin-3-ylmethyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(2-(4-tert-butylbenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(7,8-dimethyl-2-(2-methylbenzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(7,8-dimethyl-2-(4-phenoxybenzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(7,8-dimethyl-2-(pyridin-4-ylmethyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(2-(3-chlorobenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(7,8-dimethyl-2-(3-methylbenzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(7,8-dimethyl-2-(3-phenoxybenzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(7,8-dimethyl-2-(thiophen-2-ylmethyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(2-(4-methoxybenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(2-(4-ethylbenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(7,8-dimethyl-2-(naphthalen-1-ylmethyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   2-(8-(3-hydroxyphenyl)-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)methyl)phenol;-   3-(2-(4-isopropylbenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(2-(furan-2-ylmethyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(2-(2-chlorobenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(2-(3-hydroxybenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(2-(4-chlorobenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(7,8-dimethyl-2-(naphthalen-2-ylmethyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(2-(3-(benzyloxy)benzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(7,8-dimethyl-2-(4-(pyridin-4-yl)benzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(2-(2,3-dichlorobenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(7,8-dimethyl-2-(quinolin-2-ylmethyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(7,8-dimethyl-2-(2-(pyridin-4-yl)benzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(2-(4-(benzyloxy)benzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(7,8-dimethyl-2-(3-(pyridin-4-yl)benzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   methyl    4-(8-(3-hydroxyphenyl)-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)methyl)benzoate;-   3-(2-(4-(dimethylamino)benzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(7,8-dimethyl-2-(4-(pyridin-3-yl)benzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(7,8-dimethyl-2-(quinolin-3-ylmethyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   methyl    3-(8-(3-hydroxyphenyl)-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)methyl)benzoate;-   3-(2-(4-(1H-imidazol-1-yl)benzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(2-(biphenyl-4-ylmethyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(7,8-dimethyl-2-(quinolin-4-ylmethyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(7,8-dimethyl-2-(2,4,5-trimethylbenzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;    or-   3-(2-(4-hydroxybenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;

or a pharmaceutically acceptable salt thereof.

More preferably, the compound of formula I is:

-   3-((2R,3R,7S,9αS)-2,3-dimethyl-7-phenyl-octahydro-1H-quinolizin-2-yl)phenol;-   1-((7R,8R,9αR)-8-(3-hydroxyphenyl)-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)-2-phenylethanone;-   3-((7R,8R,9αR)-7,8-dimethyl-2-phenethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   ((7R,8R,9αR)-8-(3-hydroxyphenyl)-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)(phenyl)methanone;-   3-((7R,8R,9αR)-2-benzyl-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((7R,8R,9αR)-7,8-dimethyl-2-(phenylsulfonyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((7R,8R,9αR)-7,8-dimethyl-2-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((3S,7R,8R,9αR)-7,8-dimethyl-3-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((3S,7R,8R,9αR)-2,7,8-trimethyl-3-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   2-((3S,7R,8R,9αR)-8-(3-hydroxyphenyl)-7,8-dimethyl-3-phenyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)acetic    acid;-   3-((3S,7R,8R,9αR)-8-(3-hydroxyphenyl)-7,8-dimethyl-3-phenyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)propanoic    acid;-   3-((3S,7R,8R,9αR)-2-benzyl-7,8-dimethyl-3-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((3S,7R,8R,9αR)-2-benzyl-7,8-dimethyl-3-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)benzamide;-   3-((3S,7R,8R,9αR)-7,8-dimethyl-3-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)benzamide;-   3-((3S,7R,8R,9αR)-3-benzyl-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((3R,7R,8R,9αR)-3-benzyl-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((3S,7R,8R,9αR)-3-cyclohexyl-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((8R,9R,10αR)-2-benzyl-8,9-dimethyl-decahydropyrido[1,2-α][1,4]diazepin-9-yl)phenol;-   3-((7R,8R,9αR)-2-(3-methoxybenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((7R,8R,9αR)-7,8-dimethyl-2-(pyridin-2-ylmethyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((7R,8R,9αR)-2-(cyclohexylmethyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((7R,8R,9αR)-7,8-dimethyl-2-(4-methylbenzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((7R,8R,9αR)-2-(2,5-dimethylbenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((7R,8R,9αR)-7,8-dimethyl-2-(thiophen-3-ylmethyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((7R,8R,9αR)-2-(furan-3-ylmethyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((7R,8R,9αR)-7,8-dimethyl-2-(pyridin-3-ylmethyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((7R,8R,9αR)-2-(4-tert-butylbenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((7R,8R,9αR)-7,8-dimethyl-2-(2-methylbenzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((7R,8R,9αR)-7,8-dimethyl-2-(4-phenoxybenzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((7R,8R,9αR)-7,8-dimethyl-2-(pyridin-4-ylmethyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((7R,8R,9αR)-2-(3-chlorobenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((7R,8R,9αR)-7,8-dimethyl-2-(3-methylbenzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((7R,8R,9αR)-7,8-dimethyl-2-(3-phenoxybenzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((7R,8R,9αR)-7,8-dimethyl-2-(thiophen-2-ylmethyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((7R,8R,9αR)-2-(4-methoxybenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((7R,8R,9αR)-2-(4-ethylbenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((7R,8R,9αR)-7,8-dimethyl-2-(naphthalen-1-ylmethyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   2-(((7R,8R,9αR)-8-(3-hydroxyphenyl)-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)methyl)phenol;-   3-((7R,8R,9αR)-2-(4-isopropylbenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((7R,8R,9αR)-2-(furan-2-ylmethyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((7R,8R,9αR)-2-(2-chlorobenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((7R,8R,9αR)-2-(3-hydroxybenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((7R,8R,9αR)-2-(4-chlorobenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((7R,8R,9αR)-7,8-dimethyl-2-(naphthalen-2-ylmethyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((7R,8R,9αR)-2-(3-(benzyloxy)benzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((7R,8R,9αR)-7,8-dimethyl-2-(4-(pyridin-4-yl)benzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((7R,8R,9αR)-2-(2,3-dichlorobenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((7R,8R,9αR)-7,8-dimethyl-2-(quinolin-2-ylmethyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((7R,8R,9αR)-7,8-dimethyl-2-(2-(pyridin-4-yl)benzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((7R,8R,9αR)-2-(4-(benzyloxy)benzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((7R,8R,9αR)-7,8-dimethyl-2-(3-(pyridin-4-yl)benzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   methyl    4-(((7R,8R,9αR)-8-(3-hydroxyphenyl)-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)methyl)benzoate;-   3-((7R,8R,9αR)-2-(4-(dimethylamino)benzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((7R,8R,9αR)-7,8-dimethyl-2-(4-(pyridin-3-yl)benzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((7R,8R,9αR)-7,8-dimethyl-2-(quinolin-3-ylmethyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   methyl    3-(((7R,8R,9αR)-8-(3-hydroxyphenyl)-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)methyl)benzoate;-   3-((7R,8R,9αR)-2-(4-(1H-imidazol-1-yl)benzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((7R,8R,9αR)-2-(biphenyl-4-ylmethyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((7R,8R,9αR)-7,8-dimethyl-2-(quinolin-4-ylmethyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((7R,8R,9αR)-7,8-dimethyl-2-(2,4,5-trimethylbenzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;    or-   3-((7R,8R,9αR)-2-(4-hydroxybenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;

or a pharmaceutically acceptable salt thereof.

In still more preferred embodiments, the compound of formula I is:

-   3-(2,3-dimethyl-7-phenyl-octahydro-1H-quinolizin-2-yl)phenol;-   (8-(3-hydroxyphenyl)-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)(phenyl)methanone;-   3-(2-benzyl-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(7,8-dimethyl-3-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(7,8-dimethyl-3-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)benzamide;-   3-(3-cyclohexyl-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(2-(cyclohexylmethyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(7,8-dimethyl-2-(thiophen-2-ylmethyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(7,8-dimethyl-2-(2-(pyridin-4-yl)benzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(2-(2-chlorobenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   2-(8-(3-hydroxyphenyl)-7,8-dimethyl-3-phenyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)acetic    acid;-   3-(7,8-dimethyl-2-(2-methylbenzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(2-(3-chlorobenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(7,8-dimethyl-2-(3-methylbenzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;    or-   2-(8-(3-hydroxyphenyl)-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)methyl)phenol;

or a pharmaceutically acceptable salt thereof.

More preferably the compound of formula I is:

-   3-((2R,3R,7S,9αS)-2,3-dimethyl-7-phenyl-octahydro-1H-quinolizin-2-yl)phenol;-   ((7R,8R,9αR)-8-(3-hydroxyphenyl)-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)(phenyl)methanone;-   3-((7R,8R,9αR)-2-benzyl-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((3S,7R,8R,9αR)-7,8-dimethyl-3-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((3S,7R,8R,9αR)-7,8-dimethyl-3-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)benzamide;-   3-((3S,7R,8R,9αR)-3-cyclohexyl-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((7R,8R,9αR)-2-(cyclohexylmethyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((7R,8R,9αR)-7,8-dimethyl-2-(thiophen-2-ylmethyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((7R,8R,9αR)-7,8-dimethyl-2-(2-(pyridin-4-yl)benzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((7R,8R,9αR)-2-(2-chlorobenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   2-((3S,7R,8R,9αR)-8-(3-hydroxyphenyl)-7,8-dimethyl-3-phenyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)acedc    acid;-   3-((7R,8R,9αR)-7,8-dimethyl-2-(2-methylbenzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((7R,8R,9αR)-2-(3-chlorobenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((7R,8R,9αR)-7,8-dimethyl-2-(3-methylbenzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;    or-   2-(((7R,8R,9αR)-8-(3-hydroxyphenyl)-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)methyl)phenol;

or a pharmaceutically acceptable salt thereof.

In yet more preferred embodiments, the compound of formula I is:

-   3-(2,3-dimethyl-7-phenyl-octahydro-1H-quinolizin-2-yl)phenol;-   (8-(3-hydroxyphenyl)-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)(phenyl)methanone;-   3-(2-benzyl-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(7,8-dimethyl-3-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(7,8-dimethyl-3-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)benzamide;-   3-(3-cyclohexyl-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(2-(cyclohexylmethyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(7,8-dimethyl-2-(thiophen-2-ylmethyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(7,8-dimethyl-2-(2-(pyridin-4-yl)benzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;    or-   3-(2-(2-chlorobenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;

or a pharmaceutically acceptable salt thereof.

More preferably, the compound of formula I is:

-   3-((2R,3R,7S,9αS)-2,3-dimethyl-7-phenyl-octahydro-1H-quinolizin-2-yl)phenol;-   ((7R,8R,9αR)-8-(3-hydroxyphenyl)-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)(phenyl)methanone;-   3-((7R,8R,9αR)-2-benzyl-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((3S,7R,8R,9αR)-7,8-dimethyl-3-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((3S,7R,8R,9αR)-7,8-dimethyl-3-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)benzamide;-   3-((3S,7R,8R,9αR)-3-cyclohexyl-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((7R,8R,9αR)-2-(cyclohexylmethyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((7R,8R,9αR)-7,8-dimethyl-2-(thiophen-2-ylmethyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((7R,8R,9αR)-7,8-dimethyl-2-(2-(pyridin-4-yl)benzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;    or-   3-((7R,8R,9αR)-2-(2-chlorobenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;

or a pharmaceutically acceptable salt thereof.

In still more preferred embodiments, the compound of formula I is:

-   3-(2,3-dimethyl-7-phenyl-octahydro-1H-quinolizin-2-yl)phenol;-   (8-(3-hydroxyphenyl)-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)    (phenyl)methanone;-   3-(2-benzyl-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(7,8-dimethyl-3-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;    or-   3-(7,8-dimethyl-3-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)benzamide;

or a pharmaceutically acceptable salt thereof.

More preferably the compound of formula I is:

-   3-((2R,3R,7S,9αS)-2,3-dimethyl-7-phenyl-octahydro-1H-quinolizin-2-yl)phenol;-   ((7R,8R,9αR)-8-(3-hydroxyphenyl)-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)(phenyl)methanone;-   3-((7R,8R,9αR)-2-benzyl-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((3S,7R,8R,9αR)-7,8-dimethyl-3-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;    or-   3-((3S,7R,8R,9αR)-7,8-dimethyl-3-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)benzamide;

or a pharmaceutically acceptable salt thereof.

In an alternate embodiment, the present invention provides compounds offormula III:

-   -   wherein:        -   R¹ is —OH, —OR^(a), —CH₂OH, —C(═O)OR⁶, —C(═O)NR⁶R⁷, or            —NR⁶R⁷;        -   R² and R³ are each independently alkyl or alkenyl;        -   R⁴ is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl,            heteroaryl, aralkyl, alkylaralkyl, or heteroarylalkyl;        -   X is CH₂ or NR⁵;        -   R⁵ is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl,            heteroaryl, aralkyl, alkylaralkyl, heteroarylalkyl,            heterocycloalkylalkyl, —C(═O)OR^(8a), —S(═O)₂R^(8a),            —C(═O)R^(8b), or —C(═O)NR^(8b)R^(8c);        -   R⁶ is H, alkyl, cycloalkyl, alkylcycloalkyl, or aralkyl;        -   R⁷ is H, alkyl, aralkyl, or aryl;        -   R^(8a) is alkyl, cycloalkyl, cycloalkylalkyl, heteroaryl,            heteroarylalkyl, aralkyl, or aryl;        -   R^(8b) and R^(8c) are each independently H, alkyl,            cycloalkyl, cycloalkylalkyl, heteroaryl, heterocycloalkyl,            heterocycloalkylalkyl, heteroarylalkyl, aralkyl, or aryl; or            R^(8b) and R^(8c) taken together with the nitrogen atom to            which they are connected form a 4- to 8-membered            heterocycloalkyl ring;        -   R^(a) is a hydroxyl protecting group;        -   m is 1 or 2; and        -   n is 0, 1, or 2;        -   with the provisos that:            -   at least one of m and n is other than 2; and            -   when X is NR⁵, then n is 1 or 2;        -   or a pharmaceutically acceptable salt thereof.

In certain preferred embodiments, the compounds of formula III have thestructure Ma:

-   -   wherein:        -   R¹ is —OH, —CH₂OH, —C(═O)OR⁶, —C(═O)NR⁶R⁷, or —NR⁶R⁷;        -   R² and R³ are each independently alkyl or alkenyl;        -   R⁴ is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl,            heteroaryl, aralkyl, alkylaralkyl, or heteroarylalkyl;        -   X is CH₂ or NR⁵;        -   R⁵ is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl,            heteroaryl, aralkyl, alkylaralkyl, heteroarylalkyl,            heterocycloalkylalkyl, —C(═O)OR^(8a), —S(═O)₂R^(8a),            —C(═O)R^(8b), or —C(═O)NR^(8b)R^(8c);        -   R⁶ is H, alkyl, cycloalkyl, alkylcycloalkyl, or aralkyl;        -   R⁷ is H, alkyl, aralkyl, or aryl;        -   R^(8a) is alkyl, cycloalkyl, cycloalkylalkyl, heteroaryl,            heteroarylalkyl, aralkyl, or aryl;        -   R^(8b) and R^(8c) are each independently H, alkyl,            cycloalkyl, cycloalkylalkyl, heteroaryl, heterocycloalkyl,            heterocycloalkylalkyl, heteroarylalkyl, aralkyl, or aryl; or            R^(8b) and R^(8c) taken together with the nitrogen atom to            which they are connected form a 4- to 8-membered            heterocycloalkyl ring;        -   m is 1 or 2; and        -   n is 0, 1, or 2;        -   with the provisos that:            -   at least one of m and n is other than 2; and            -   when X is NR⁵, then n is 1 or 2;        -   or a pharmaceutically acceptable salt thereof.

More preferably when compounds of formula III have the structure Ma, R¹is —OH, —C(═O)OR⁶, —C(═O)NR⁶R⁷, or —NR⁶R⁷, yet more preferably —OH,—C(═O)NR⁶R⁷, or —NR⁶R⁷, still more preferably —OH or —C(═O)NR⁶R⁷.

In certain preferred embodiments of compounds of formula III, R² and R³are each independently C₁-C₆alkyl or C₂-C₆alkenyl, more preferablyC₁-C₃alkyl or C₂-C₃alkenyl, more preferably still C₁-C₃alkyl, yet morepreferably C₁alkyl, still more preferably methyl.

In certain preferred embodiments of compounds of formula III, R⁴ is H,alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, aralkyl,alkylaralkyl, or heteroarylalkyl, with H, alkyl, cycloalkyl, aryl, oraralkyl being more preferred. When R⁴ is alkyl, it is preferablyC₁-C₆alkyl, more preferably C₁-C₃alkyl, yet more preferably C₃alk-2-yl,still more preferably isopropyl. When R⁴ is cycloalkyl, it is preferablyC₃-C₁₀cycloalkyl, more preferably C₃-C₈cycloalkyl, yet more preferablyC₃-C₆cycloalkyl, still more preferably C₅-C₆cycloalkyl, still morepreferably optionally substituted cyclopentyl or optionally substitutedcyclohexyl. When R⁴ is cycloalkylalkyl, it is preferablyC₃-C₁₀cycloalkylC₁-C₆alkyl, more preferably C₃-C₈cycloalkylC₁-C₃alkyl,yet more preferably C₃-C₆cycloalkylC₁-C₃alkyl, still more preferablyC₅-C₆cycloalkylC₁-C₃alkyl, still more preferably optionally substitutedcyclopentylmethyl or optionally substituted cyclohexylmethyl. When R⁴ isaryl, it is preferably C₆-C₁₀aryl, more preferably C₆aryl, yet morepreferably phenyl. When R⁴ is heteroaryl, it is preferablyC₅-C₁₀heteroaryl, more preferably C₅-C₆heteroaryl, still more preferablypyridinyl or thienyl. When R⁴ is aralkyl, it is preferablyC₆-C₁₀arylC₁-C₆alkyl, more preferably C₆-C₁₀arylC₁-C₃alkyl, yet morepreferably C₆arylC₁-C₃alkyl, still more preferably C₆arylC₁alkyl, yetmore preferably optionally substituted benzyl. When R⁴ is alkylaralkyl,it is preferably C₁-C₆alkylC₆-C₁₀arylC₁-C₆alkyl, more preferablyC₁-C₄alkylC₆-C₁₀arylC₁-C₃alkyl, yet more preferablyC₁-C₄alkylC₆arylC₁-C₃alkyl, still more preferably C₁alkylC₆arylC₁alkyl,yet more preferably optionally substituted methylbenzyl. When R⁴ isheteroarylalkyl, it is preferably C₅-C₁₀heteroarylC₁-C₆alkyl, morepreferably C₅-C₁₀heteroarylC₁-C₃alkyl, yet more preferablyC₅-C₆heteroarylC₁-C₃alkyl, still more preferably C₅-C₆heteroarylC₁alkyl.In certain preferred embodiments, R⁴ is H.

In certain preferred embodiments of compounds of formula III, X is NR⁵.

In certain preferred embodiments of compounds of formula III, R⁵ is H,alkyl, aryl, cycloalkylalkyl, aralkyl, alkylaralkyl, heteroarylalkyl,heterocycloalkylalkyl, —S(═O)₂R^(8a), —C(═O)R^(8b), or—C(═O)NR^(8b)R^(8c), more preferably —C(═O)R^(8b) or —S(═O)₂R^(8a),still more preferably —C(═O)R^(8b). In other preferred embodiments, R⁵is H, alkyl, aryl, cycloalkylalkyl, aralkyl, alkylaralkyl,heteroarylalkyl, or heterocycloalkylalkyl, more preferablyheterocycloalkylalkyl or aralkyl, with heterocycloalkylalkyl being evenmore preferred. When R⁵ is alkyl, it is preferably C₁-C₆alkyl, morepreferably C₁-C₃alkyl, yet more preferably C₁alkyl, still morepreferably methyl optionally substituted with carboxy. When R⁵ iscycloalkyl, it is preferably C₃-C₁₀cycloalkyl, more preferablyC₃-C₈cycloalkyl, yet more preferably C₃-C₆cycloalkyl, still morepreferably C₅-C₆cycloalkyl, still more preferably optionally substitutedcyclopentyl or optionally substituted cyclohexyl. When R⁵ iscycloalkylalkyl, it is preferably C₃-C₁₀cycloalkylC₁-C₆alkyl, morepreferably C₃-C₈cycloalkylC₁-C₃alkyl, yet more preferablyC₃-C₆cycloalkylC₁-C₃alkyl, still more preferablyC₅-C₆cycloalkylC₁-C₃alkyl, still more preferably optionally substitutedcyclopentylmethyl or optionally substituted cyclohexylmethyl. When R⁵ isaryl, it is preferably C₆-C₁₀aryl, more preferably C₆aryl, yet morepreferably phenyl. When R⁵ is heteroaryl, it is preferablyC₅-C₁₀heteroaryl, more preferably C₅-C₆heteroaryl, even more preferablypyridinyl or pyrimidinyl. When R⁵ is aralkyl, it is preferablyC₆-C₁₀arylC₁-C₆alkyl, more preferably C₆-C₁₀arylC₁-C₃alkyl, yet morepreferably C₆arylC₁-C₃alkyl, still more preferably C₆arylC₁alkyl, yetmore preferably benzyl optionally substituted with C₁-C₆alkyl, halo,hydroxy, or heteroaryl, yet more preferably 2-chlorobenzyl,3-chlorobenzyl, 2-hydroxylbenzyl, 2-methylbenzyl, 3-methylbenzyl,2,4,5-trimethylbenzyl, or 2-(pyrid-4-yl)benzyl. When R⁵ is alkylaralkyl,it is preferably C₁-C₆alkylC₆-C₁₀arylC₁-C₆alkyl, more preferablyC₁-C₄alkylC₆-C₁₀arylC₁-C₃alkyl, yet more preferablyC₁-C₄alkylC₆arylC₁-C₃alkyl, still more preferably C₁alkylC₆arylC₁alkyl,yet more preferably optionally substituted methylbenzyl. When R⁵ isheteroarylalkyl, it is preferably C₅-C₁₀heteroarylC₁-C₆alkyl, morepreferably C₅-C₁₀heteroarylC₁-C₃alkyl, yet more preferablyC₅-C₆heteroarylC₁-C₃alkyl, still more preferably C₅-C₆heteroarylC₁alkyl,yet more preferably optionally substituted thienylmethyl. When R⁵ isheterocycloalkylalkyl, it is preferably C₅-C₂₀heterocycloalkylalkyl,more preferably C₉-C₁₄heterocycloalkylalkyl, yet more preferablyoptionally substituted tetrahydroquinolinylmethyl or optionallysubstituted tetrahydroisoquinolinylmethyl, still more preferablyoptionally substituted 1,2,3,4-tetrahydroquinolin-3-ylmethyl oroptionally substituted 1,2,3,4-tetrahydroisoquinolin-3-ylmethyl, evenmore preferably optionally substituted1,2,3,4-tetrahydroisoquinolin-3-ylmethyl, with6-hydroxy-1,2,3,4-tetrahydroisoquinolin-3-ylmethyl being even morepreferred. In certain preferred embodiments, R⁵ is H. In certain otherembodiments, when R⁵ is optionally substituted, it is preferablysubstituted with at least one hydroxy, alkyl, or —C(═O)N(alkyl)(alkyl),more preferably with at least one hydroxy.

When R⁵ is optionally substituted 1,2,3,4-tetrahydroquinolin-3-ylmethyl,a stereoisomeric center exists at the 3-position of thetetrahydroquinoline ring. As such, the1,2,3,4-tetrahydroquinolin-3-ylmethyl moiety may exist as a racemate, asingle stereoisomeric moiety, or any non-racemic combination of the (R-)and (S)-stereoisomeric moieties. In certain preferred embodiments, the1,2,3,4-tetrahydroquinolin-3-ylmethyl moiety is present in an opticallyenriched form, more preferably optically enriched in its (R)— form;still more preferably substantially optically enriched in its (R)— form;and most preferably as substantially optically pure1,2,3,4-tetrahydroquinolin-3(R)-ylmethyl. In particularly preferredembodiments, R⁵ is substantially optically pure:

When R⁵ is optionally substituted tetrahydroisoquinolinylmethyl, astereoisomeric center exists at the 3-position of thetetrahydroisoquinoline ring. As such, the1,2,3,4-tetrahydroisoquinolin-3-ylmethyl moiety may exist as a racemate,a single stereoisomeric moiety, or any non-racemic combination of the(R)- and (S)-stereoisomeric moieties. In certain preferred embodiments,the 1,2,3,4-tetrahydroisoquinolin-3-ylmethyl moiety is present in anoptically enriched form, more preferably optically enriched in its (R)—form; still more preferably substantially optically enriched in its (R)—form; and most preferably as substantially optically pure1,2,3,4-tetrahydroisoquinolin-3(R)-ylmethyl. In other preferredembodiments, R⁵ is substantially optically pure:

In certain preferred embodiments of compounds of formula III, R⁶ is H,alkyl, cycloalkyl, alkylcycloalkyl, or aralkyl, with H, alkyl,alkylcycloalkyl, or aralkyl being more preferred. When R⁶ is alkyl, itis preferably C₁-C₆alkyl, more preferably C₁-C₃alkyl, yet morepreferably C₁alkyl, still more preferably methyl. When R⁶ is cycloalkyl,it is preferably C₃-C₁₀cycloalkyl, more preferably C₃-C₈cycloalkyl, yetmore preferably C₃-C₆cycloalkyl, still more preferably C₅-C₆cycloalkyl,still more preferably optionally substituted cyclopentyl or optionallysubstituted cyclohexyl. When R⁶ is alkylcycloalkyl, it is preferablyC₁-C₆alkylC₃-C₁₀cycloalkylC₁-C₆alkyl, more preferablyC₁-C₄alkylC₃-C₈cycloalkylC₁-C₃alkyl, yet more preferablyC₁-C₄alkylC₃-C₆cycloalkylC₁-C₃alkyl, still more preferablyC₁alkylC₅-C₆cycloalkylC₁alkyl, yet more preferably optionallysubstituted methylcyclopentylmethyl or optionally substitutedmethylcyclohexylmethyl. When R⁶ is aralkyl, it is preferablyC₆-C₁₀arylC₁-C₆alkyl, more preferably C₆-C₁₀arylC₁-C₃alkyl, yet morepreferably C₆arylC₁-C₃alkyl, still more preferably C₆arylC₁alkyl, yetmore preferably benzyl. In certain preferred embodiments, R⁶ is H.

In preferred embodiments of compounds of formula III, m is 1. Also inpreferred embodiments of compounds of formula I, n is 0 or 1. In certainpreferred embodiments, m and n are each 1.

In some preferred embodiments of compounds of formula III, at least oneof R⁴ and R⁵ is H.

In certain preferred embodiments of compounds of formula III, R⁷ is H,alkyl, aralkyl, or aryl, with H being more preferred. When R⁷ is alkyl,it is preferably C₁-C₆alkyl, more preferably C₁-C₃alkyl, yet morepreferably C₁alkyl, still more preferably methyl. When R⁷ is aralkyl, itis preferably C₆-C₁₀arylC₁-C₆alkyl, more preferablyC₆-C₁₀arylC₁-C₃alkyl, yet more preferably C₆arylC₁-C₃alkyl, still morepreferably C₆arylC₁alkyl, yet more preferably benzyl. When R⁷ is aryl,it is preferably C₆-C₁₀aryl, more preferably C₆aryl, yet more preferablyphenyl.

In certain preferred embodiments of compounds of formula III, R^(8a) isalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl,aralkyl, or aryl. When R^(8a) is alkyl, it is preferably C₁-C₆alkyl,more preferably C₁-C₃alkyl, yet more preferably C₁alkyl, still morepreferably methyl. When R^(8a) is cycloalkyl, it is preferablyC₃-C₁₀cycloalkyl, more preferably C₃-C₈cycloalkyl, yet more preferablyC₃-C₆cycloalkyl, still more preferably C₅-C₆cycloalkyl, still morepreferably optionally substituted cyclopentyl or optionally substitutedcyclohexyl. When R^(8a) is cycloalkylalkyl, it is preferablyC₃-C₁₀cycloalkylC₁-C₆alkyl, more preferably C₃-C₈cycloalkylC₁-C₃alkyl,yet more preferably C₃-C₆cycloalkylC₁-C₃alkyl, still more preferablyC₅-C₆cycloalkylC₁-C₃alkyl, still more preferably cyclopentylC₁-C₃alkylor cyclohexylC₁-C₃alkyl, yet more preferably optionally substitutedcyclopentylmethyl or optionally substituted cyclohexylmethyl. WhenR^(8a) is aryl, it is preferably C₆-C₁₀aryl, more preferably C₆aryl, yetmore preferably phenyl. When R^(8a) is heteroaryl, it is preferablyC₅-C₁₀heteroaryl, more preferably C₅-C₆heteroaryl, even more preferablypyridinyl or pyrimidinyl. When R^(8a) is aralkyl, it is preferablyC₆-C₁₀arylC₁-C₆alkyl, more preferably C₆-C₁₀arylC₁-C₃alkyl, yet morepreferably C₆arylC₁-C₃alkyl, still more preferably C₆arylC₁alkyl, yetmore preferably benzyl. When R^(8a) is heteroarylalkyl, it is preferablyC₅-C₁₀heteroarylC₁-C₆ alkyl, more preferably C₅-C₁₀heteroarylC₁-C₃alkyl,yet more preferably C₅-C₆heteroarylC₁-C₃alkyl, still more preferablyC₅-C₆heteroarylC₁alkyl.

In certain preferred embodiments of compounds of formula III, R^(8b) andR^(8c) are each independently H, alkyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl,aralkyl, or aryl, more preferably aryl, heterocycloalkyl,heterocycloalkylalkyl, or aralkyl, with heterocycloalkyl,heterocycloalkylalkyl, or aralkyl being more preferred. In some otherpreferred embodiments of compounds of formula III, R^(8b) and R^(8c) areeach independently aryl or aralkyl. In still other preferredembodiments, R^(8b) and R^(8c) are each independently heterocycloalkyl,aryl, or aralkyl, more preferably heterocycloalkyl. When R^(8b) orR^(8c) is alkyl, it is preferably C₁-C₆alkyl, more preferablyC₁-C₃alkyl, yet more preferably C₁alkyl, still more preferably methyl.When R^(8b) or R^(8c) is cycloalkyl, it is preferably C₃-C₁₀cycloalkyl,more preferably C₃-C₈cycloalkyl, yet more preferably C₃-C₆cycloalkyl,still more preferably C₅-C₆cycloalkyl, still more preferably optionallysubstituted cyclopentyl or optionally substituted cyclohexyl. WhenR^(8b) or R^(8c) is cycloalkylalkyl, it is preferablyC₃-C₁₀cycloalkylC₁-C₆alkyl, more preferably C₃-C₈cycloalkylC₁-C₃alkyl,yet more preferably C₃-C₆cycloalkylC₁-C₃alkyl, still more preferablyC₅-C₆cycloalkylC₁-C₃alkyl, still more preferably optionally substitutedcyclopentylmethyl or optionally substituted cyclohexylmethyl. WhenR^(8b) or R^(8c) is aryl, it is preferably C₆-C₁₀aryl, more preferablyC₆aryl, yet more preferably phenyl. When R^(8b) or R^(8c) is heteroaryl,it is preferably C₅-C₁₀heteroaryl, more preferably C₅-C₆heteroaryl, evenmore preferably pyridinyl. When R^(8b) or R^(8c) is aralkyl, it ispreferably C₆-C₁₀arylC₁-C₆alkyl, more preferably C₆-C₁₀arylC₁-C₃alkyl,yet more preferably C₆arylC₁-C₃alkyl, still more preferablyC₆arylC₂alkyl, yet more preferably optionally substituted phenethyl,with 1-(4-hydroxyphenyl)ethyl being even more preferred. When R^(8b) orR^(8c) is heteroarylalkyl, it is preferably C₅-C₁₀heteroarylC₁-C₆alkyl,more preferably C₅-C₁₀heteroarylC₁-C₃alkyl, yet more preferablyC₅-C₆heteroarylC₁-C₃alkyl, still more preferably C₅-C₆heteroarylC₁alkyl.When R^(8b) or R^(8c) is heterocycloalkylalkyl, it is preferablyC₅-C₁₀heterocycloalkylC₁-C₆alkyl, more preferablyC₅-C₁₀heterocycloalkylC₁-C₃alkyl, still more preferablyC₅-C₁₀heterocycloalkylC₁alkyl, yet more preferablyC₅-C₁₀heterocycloalkylmethyl, even more preferably optionallysubstituted tetrahydroquinolinylmethyl or optionally substitutedtetrahydroisoquinolinylmethyl, still more preferably optionallysubstituted 1,2,3,4-tetrahydroquinolin-3-ylmethyl or optionallysubstituted 1,2,3,4-tetrahydroisoquinolin-3-ylmethyl, even morepreferably optionally substituted1,2,3,4-tetrahydroisoquinolin-3-ylmethyl, with6-hydroxy-1,2,3,4-tetrahydroisoquinolin-3-ylmethyl being even morepreferred. When R^(8b) or R^(8c) is heterocycloalkyl, it is preferablyC₅-C₁₅heterocycloalkyl, more preferably C₉-C₁₄heterocycloalkyl, yet morepreferably optionally substituted tetrahydroquinolinylmethyl oroptionally substituted tetrahydroisoquinolinylmethyl, still morepreferably optionally substituted 1,2,3,4-tetrahydroquinolin-3-ylmethylor optionally substituted 1,2,3,4-tetrahydroisoquinolin-3-ylmethyl, evenmore preferably optionally substituted1,2,3,4-tetrahydroisoquinolin-3-ylmethyl, with6-hydroxy-1,2,3,4-tetrahydroisoquinolin-3-ylmethyl being even morepreferred. In certain other embodiments, when R^(8b) or R^(8c) isoptionally substituted, it is preferably substituted with at least onehydroxy, alkyl, or —C(═O)N(alkyl)(alkyl), more preferably with at leastone hydroxy.

When R^(8b) or R^(8c) is optionally substituted1,2,3,4-tetrahydroquinolin-3-ylmethyl, a stereoisomeric center exists atthe 3-position of the tetrahydroquinoline ring. As such, the1,2,3,4-tetrahydroquinolin-3-ylmethyl moiety may exist as a racemate, asingle stereoisomeric moiety, or any non-racemic combination of the (R)-and (S)-stereoisomeric moieties. In certain preferred embodiments, the1,2,3,4-tetrahydroquinolin-3-ylmethyl moiety is present in an opticallyenriched configuration, more preferably optically enriched in its(R)-configuration; still more preferably substantially opticallyenriched in its (R)-configuration; and most preferably as substantiallyoptically pure 1,2,3,4-tetrahydroquinolin-3(R)-ylmethyl. In otherpreferred embodiments, R^(8b) or R^(8c) is substantially optically pure:

When R^(8b) or R^(8c) is optionally substitutedtetrahydroisoquinolinylmethyl, a stereocenter exists at the 3-positionof the tetrahydroisoquinoline ring. As such, the1,2,3,4-tetrahydroisoquinolin-3-ylmethyl moiety may exist as a racemate,a single stereoisomeric moiety, or any non-racemic combination of the(R)- and (S)-stereoisomeric moieties. In certain preferred embodiments,the 1,2,3,4-tetrahydroisoquinolin-3-ylmethyl moiety is present in anoptically enriched configuration, more preferably optically enriched inits (R)-configuration; still more preferably substantially opticallyenriched in its (R)-configuration; and most preferably as substantiallyoptically pure 1,2,3,4-tetrahydroisoquinolin-3(R)-ylmethyl. In otherpreferred embodiments, R^(8b) or R^(8c) is substantially optically pure:

When R^(8b) or R^(8c) is optionally substituted1,2,3,4-tetrahydroquinolin-3-yl, a stereoisomeric center exists at the3-position of the tetrahydroquinoline ring. As such, the1,2,3,4-tetrahydroquinolin-3-yl moiety may exist as a racemate, a singlestereoisomeric moiety, or any non-racemic combination of the (R)- and(S)-stereoisomeric moieties. In certain preferred embodiments, the1,2,3,4-tetrahydroquinolin-3-yl moiety is present in an opticallyenriched configuration, more preferably optically enriched in its(R)-configuration; still more preferably substantially opticallyenriched in its (R)-configuration; and most preferably as substantiallyoptically pure 1,2,3,4-tetrahydroquinolin-3(R)-yl. In other preferredembodiments, R^(8b) or R^(8c) is substantially optically pure:

When R^(8b) or R^(8c) is optionally substituted tetrahydroisoquinolinyl,a stereocenter exists at the 3-position of the tetrahydroisoquinolinering. As such, the 1,2,3,4-tetrahydroisoquinolin-3-yl moiety may existas a racemate, a single stereoisomeric moiety, or any non-racemiccombination of the (R)- and (S)-stereoisomeric moieties. In certainpreferred embodiments, the 1,2,3,4-tetrahydroisoquinolin-3-yl moiety ispresent in an optically enriched configuration, more preferablyoptically enriched in its (R)-configuration; still more preferablysubstantially optically enriched in its (R)-configuration; and mostpreferably as substantially optically pure1,2,3,4-tetrahydroisoquinolin-3(R)-yl. In other preferred embodiments,R^(8b) or R^(8c) is substantially optically pure:

In certain other preferred embodiments of compounds of formula III,R^(8b) and R^(8c), taken together with the nitrogen atom to which theyare connected, form a 4- to 8-membered heterocycloalkyl ring, morepreferably a 5- to 7-membered heterocycloalkyl ring, more preferablystill, a 5- to 6-membered heterocycloalkyl ring, yet more preferably anoptionally substituted morpholine ring.

In some preferred embodiments, the compounds of formula III have thestructure corresponding to formula IVa:

In some preferred embodiments, the compounds of formula I have thestructure corresponding to formula IVb:

In particularly preferred embodiments, the compound of formula III is:

-   3-(4-hydroxyphenyl)-1-(8-(3-hydroxyphenyl)-3-isopropyl-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)propan-1-one;-   (7-hydroxy-1,2,3,4-tetrahydroisoquinolin-3-yl)-(8-(3-hydroxyphenyl)-3-isopropyl-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)methanone;-   3-(2,3-dimethyl-octahydro-1H-quinolizin-2-yl)phenol;-   1-(8-(3-hydroxyphenyl)-7,8-dimethyl-3-phenyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)ethanone;-   methyl-3-(2-benzyl-7,8-dimethyl-3-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)benzoate;-   3-(2-benzyl-7,8-dimethyl-3-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)benzoic    acid;-   3-(7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(3-isopropyl-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(2,7,8-trimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   1-(8-(3-hydroxyphenyl)-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)ethanone;-   1-(8-(3-hydroxyphenyl)-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)-3-phenylpropan-1-one;-   3-(7,8-dimethyl-2-(3-phenylpropyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-(7,8-dimethyl-2-(methylsulfonyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;    or-   8-(3-hydroxyphenyl)-7,8-dimethyl-N-phenyl-hexahydro-1H-pyrido[1,2-α]pyrazine-2(6H)-carboxamide;

or a pharmaceutically acceptable salt thereof.

More preferably the compound of formula III is:

-   3-(4-hydroxyphenyl)-1-((3S,7R,8R,9αR)-8-(3-hydroxyphenyl)-3-isopropyl-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)propan-1-one;-   ((R)-7-hydroxy-1,2,3,4-tetrahydroisoquinolin-3-yl)((3S,7R,8R,9αR)-8-(3-hydroxyphenyl)-3-isopropyl-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)methanone;-   3-((2R,3R,9αR)-2,3-dimethyl-octahydro-1H-quinolizin-2-yl)phenol;-   3-((2R,3R,9αS)-2,3-dimethyl-octahydro-1H-quinolizin-2-yl)phenol;-   1-((3S,7R,8R,9αR)-8-(3-hydroxyphenyl)-7,8-dimethyl-3-phenyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)ethanone;-   methyl-3-((3S,7R,8R,9αR)-2-benzyl-7,8-dimethyl-3-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)benzoate;-   3-((3S,7R,8R,9αR)-2-benzyl-7,8-dimethyl-3-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)benzoic    acid;-   3-((3R,7R,8R,9αR)-7,8-dimethyl-3-phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((7R,8R,9αR)-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((3S,7R,8R,9αR)-3-Isopropyl-7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((7R,8R,9αR)-2,7,8-trimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   1-((7R,8R,9αR)-8-(3-hydroxyphenyl)-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)ethanone;-   1-((7R,8R,9αR)-8-(3-hydroxyphenyl)-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)-3-phenylpropan-1-one;-   3-((7R,8R,9αR)-7,8-dimethyl-2-(3-phenylpropyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;-   3-((7R,8R,9αR)-7,8-dimethyl-2-(methylsulfonyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol;    or-   (7R,8R,9αR)-8-(3-hydroxyphenyl)-7,8-dimethyl-N-phenyl-hexahydro-1H-pyrido[1,2-α]pyrazine-2(6H)-carboxamide;

or a pharmaceutically acceptable salt thereof.

In other particularly preferred embodiments, the compound of formula IIIis:

-   3-(4-hydroxyphenyl)-1-(8-(3-hydroxyphenyl)-3-isopropyl-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)propan-1-one;    or-   (7-hydroxy-1,2,3,4-tetrahydroisoquinolin-3-yl)-(8-(3-hydroxyphenyl)-3-isopropyl-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)methanone,

or a pharmaceutically acceptable salt thereof.

In certain other more preferred embodiments, the compound of formula IIIis:

-   3-(4-hydroxyphenyl)-1-((3S,7R,8R,9αR)-8-(3-hydroxyphenyl)-3-isopropyl-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)propan-1-one;    or-   ((R)-7-hydroxy-1,2,3,4-tetrahydroisoquinolin-3-yl)((3S,7R,8R,9αR)-8-(3-hydroxyphenyl)-3-isopropyl-7,8-dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)methanone;

or a pharmaceutically acceptable salt thereof.

In yet other embodiments, the invention is directed to methods forbinding opioid receptors in a patient in need thereof, comprising thestep of:

-   -   administering to the patient a composition comprising an        effective amount of a compound of the invention, preferably a        compound of formula Ia or formula IIIa; or a pharmaceutically        acceptable salt thereof.

In some preferred embodiments, the present methods are directed tobinding μ, κ, or δ opioid receptors. In certain more preferredembodiments wherein μ opioid receptors are bound, the receptors arelocated in the central nervous system; in other more preferredembodiments the receptors are located peripherally to the centralnervous system. In certain other more preferred embodiments wherein κopioid receptors are bound, the receptors are located in the centralnervous system; in other more preferred embodiments the receptors arelocated peripherally to the central nervous system. In still other morepreferred embodiments wherein δ opioid receptors are bound, thereceptors are located in the central nervous system; in other morepreferred embodiments the receptors are located peripherally to thecentral nervous system. In still other preferred embodiments of methodsthat bind opioid receptors in a patient in need thereof, the bindingantagonizes the activity of the opioid receptors. In some preferredembodiments of methods that bind opioid receptors in a patient in needthereof, the compound administered exhibits activity toward the opioidreceptors. In some more preferred embodiments, the compound administereddoes not substantially cross the blood-brain barrier.

In certain embodiments of methods for binding opioid receptors in apatient in need thereof, the methods comprise the step of:

administering to the patient a composition comprising an effectiveamount of a compound of the invention, preferably a compound of formulaIa or formula IIIa. In certain embodiments, the patient is in need ofprevention or treatment of a condition or disease caused by an opioidwherein the opioid may be endogenous or exogenous. In certain preferredembodiments, the compound of the invention, preferably a compound offormula Ia or formula IIIa, may be administered in combination with aneffective amount of at least one opioid.

In other embodiments, the invention is directed to methods of preventingor treating gastrointestinal dysfunction, comprising the step of:

administering to a patient in need thereof, a composition comprising aneffective amount of a compound of the invention, preferably a compoundof formula Ia or formula IIIa, or a pharmaceutically acceptable saltthereof.

In yet other embodiments, the invention is directed to methods ofpreventing or treating ileus, comprising the step of:

administering to a patient in need thereof, a composition comprising aneffective amount of a compound of the invention, preferably a compoundof formula Ia or formula IIIa, or a pharmaceutically acceptable saltthereof. Preferably, the ileus is post-operative ileus.

In yet other embodiments, the invention is directed to methods ofpreventing or treating obesity, comprising the step of:

administering to a patient in need thereof, a composition comprising aneffective amount of a compound of the invention, preferably a compoundof formula Ia or formula IIIa, or a pharmaceutically acceptable saltthereof.

In other embodiments, the invention is directed to methods of preventingor treating a side effect associated with an opioid, comprising the stepof:

administering to a patient in need thereof, a composition comprising aneffective amount of a compound of the invention, preferably a compoundof formula Ia or formula IIIa, or a pharmaceutically acceptable saltthereof.

In certain preferred embodiments, the side effect is selected from thegroup consisting of constipation, nausea, vomiting, and combinationsthereof. In other preferred embodiments, the administering step occursbefore, during or after a step of administering at least one opioid.

In yet other embodiments, the invention is directed to methods ofpreventing or treating pain, comprising the step of:

administering to a patient in need thereof, a composition, comprising:

an effective amount of an opioid; and

an effective amount of a compound of the invention, preferably acompound of formula Ia or formula IIIa, or a pharmaceutically acceptablesalt thereof.

The compounds employed in the methods of the present invention may existin prodrug form. As used herein, “prodrug” is intended to include anycovalently bonded carriers which release the active parent drug, forexample, as according to compounds of the invention, preferablycompounds of formula Ia or formula IIIa, employed in the methods of thepresent invention in vivo when such prodrug is administered to amammalian subject. Since prodrugs are known to enhance numerousdesirable qualities of pharmaceuticals (e.g., solubility,bioavailability, manufacturing, etc.) the compounds employed in thepresent methods may, if desired, be delivered in prodrug form. Thus, thepresent invention contemplates methods of delivering prodrugs. Prodrugsof the compounds employed in the present invention, for examplecompounds of the invention, preferably compounds of formula Ia orformula IIIa, or a pharmaceutically acceptable salt thereof, may beprepared by modifying functional groups present in the compound in sucha way that the modifications are cleaved, either in routine manipulationor in vivo, to the parent compound.

Accordingly, prodrugs include, for example, compounds described hereinin which a hydroxy, amino, or carboxy group is bonded to any group that,when the prodrug is administered to a mammalian subject, cleaves to forma free hydroxyl, free amino, or carboxylic acid, respectively. Examplesinclude, but are not limited to, acetate, formate and benzoatederivatives of alcohol and amine functional groups; and alkyl,carbocyclic, aryl, and alkylaryl esters such as methyl, ethyl, propyl,iso-propyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, phenyl,benzyl, and phenethyl esters, and the like.

The compounds employed in the methods of the present invention may beprepared in a number of ways well known to those skilled in the art. Thecompounds can be synthesized, for example, by the methods describedbelow, or variations thereon as appreciated by the skilled artisan. Allprocesses disclosed in association with the present invention arecontemplated to be practiced on any scale, including milligram, gram,multigram, kilogram, multikilogram or commercial industrial scale.

As discussed in detail above, compounds employed in the present methodsmay contain one or more asymmetrically substituted carbon atoms, and maybe isolated in optically active or racemic forms. Thus, all non-racemic(e.g., any molecule having one or more stereoisomeric centers whoseconfiguration or configurations is/are optically enriched, substantiallyoptically enriched, or substantially optically pure), diastereomeric, orracemic forms and all geometric isomeric forms of a structure areintended, unless the specific stereochemistry or isomeric form isspecifically indicated. It is well known in the art how to prepare andisolate such optically active forms. For example, mixtures ofstereoisomers may be separated by standard techniques including, but notlimited to, resolution of racemic forms, normal, reverse-phase, andchiral chromatography, preferential salt formation, recrystallization,and the like, or by chiral synthesis either from chiral startingmaterials or by deliberate synthesis of target chiral centers.

As will be readily understood, functional groups present may containprotecting groups during the course of synthesis. Protecting groups areknown per se as chemical functional groups that can be selectivelyappended to and removed from functionalities, such as hydroxyl groupsand carboxy groups. These groups are present in a chemical compound torender such functionality inert to chemical reaction conditions to whichthe compound is exposed. Any of a variety of protecting groups may beemployed with the present invention. Preferred protecting groups includethe benzyloxycarbonyl group and the tert-butyloxycarbonyl groups.Preferred hydroxyl protecting groups include the benzyl and thetertiary-butyldimethylsilyl groups. Other preferred protecting groupsthat may be employed in accordance with the present invention may bedescribed in Greene, T. W. and Wuts, P. G. M., Protective Groups inOrganic Synthesis 3d. Ed., Wiley & Sons, 1991.

While not intending to be bound by any theory or theories of operation,it is contemplated that opioid side effects, such as constipation,vomiting, and nausea, may result from undesirable interaction of theopioid with peripheral opioid receptors, such as peripheral μ receptors.According to one aspect of the present invention, administration of thecompounds of the invention, preferably the compounds of formula Ia orformula IIIa, as described herein, or a pharmaceutically acceptable saltthereof, may block interaction of the opioid compounds with theperipheral receptors, thereby preventing and/or inhibiting the sideeffects, while preferably not interfering with the therapeutic effect ofthe opioid in the CNS.

As noted above, certain embodiments of the present invention involve,inter alia, an opioid compound. A wide variety of opioids is availablethat may be suitable for use in the present methods and compositions.Generally speaking, it is only necessary that the opioid provide thedesired effect (for example, pain alleviation), and be capable of beingincorporated into the present combination products and methods(discussed in detail below). In preferred embodiments, the presentmethods and compositions may involve an opioid that is selected fromalfentanil, buprenorphine, butorphanol, codeine, dezocine,dihydrocodeine, fentanyl, hydrocodone, hydromorphone, levorphanol,meperidine (pethidine), methadone, morphine, nalbuphine, oxycodone,oxymorphone, pentazocine, propiram, propoxyphene, sufentanil and/ortramadol, and/or mixtures thereof. More preferably, the opioid isselected from morphine, codeine, oxycodone, hydrocodone, dihydrocodeine,propoxyphene, fentanyl, tramadol, and/or mixtures thereof.

The opioid component of the present methods and compositions may furtherinclude one or more other active ingredients that may be conventionallyemployed in analgesic and/or cough-cold-antitussive combinationproducts. Such conventional ingredients include, for example, aspirin,acetaminophen, phenylpropanolamine, phenylephrine, chlorpheniramine,caffeine, and/or guaifenesin. Typical or conventional ingredients thatmay be included in the opioid component are described, for example, inthe Physicians' Desk Reference, 1999, the disclosure of which is herebyincorporated herein by reference, in its entirety.

In addition, the opioid component may further include one or morecompounds that may be designed to enhance the analgesic potency of theopioid and/or to reduce analgesic tolerance development. Such compoundsinclude, for example, dextromethorphan or other NMDA antagonists (Mao,M. J., et al., Pain, 1996, 67, 361), L-364, 718 and other CCKantagonists (Dourish, C. T., et al., Eur. J. Pharmacol., 1988, 147,469), NOS inhibitors (Bhargava, H. N., et al., Neuropeptides, 1996, 30,219), PKC inhibitors (Bilsky, E. J., et al., J. Pharmacol. Exp. Ther.,1996, 277, 484), and dynorphin antagonists or antisera (Nichols, M. L.,et al., Pain, 1997, 69, 317). The disclosures of each of the foregoingdocuments are hereby incorporated herein by reference, in theirentireties.

Other opioids, optional conventional opioid components, and optionalcompounds for enhancing the analgesic potency of the opioid and/or forreducing analgesic tolerance development, that may be employed in themethods and compositions of the present invention, in addition to thoseexemplified above, would be readily apparent to one of ordinary skill inthe art, once armed with the teachings of the present disclosure.

Although the compounds of the present invention may be administered asthe pure chemicals, it is preferable to present the active ingredient asa pharmaceutical composition. The invention thus further provides apharmaceutical composition comprising an effective amount of one or moreof the compounds of the invention, preferably one or more compounds offormula Ia or formula IIIa, as described herein, together with one ormore pharmaceutically acceptable carriers therefore and, optionally,other therapeutic and/or prophylactic ingredients. The carrier(s) mustbe acceptable in the sense of being compatible with the otheringredients of the composition and not deleterious to the recipientthereof.

The compounds of the invention may be administered in an effectiveamount by any of the conventional techniques well-established in themedical field. The compounds employed in the methods of the presentinvention including, for example, opioids and the compounds of theinvention, preferably compounds of formula Ia or formula IIIa, asdescribed herein, or a pharmaceutically acceptable salt thereof, may beadministered by any means that results in the contact of the activeagent(s) with the relevant site or site(s) of action in the body of apatient. The compounds may be administered by any conventional meansavailable for use in conjunction with pharmaceuticals, either asindividual therapeutic agents or in a combination of therapeutic agents.For example, they may be administered as the sole active agents in apharmaceutical composition, or they can be used in combination withother therapeutically active ingredients.

The compounds are preferably combined with a pharmaceutical carrierselected on the basis of the chosen route of administration and standardpharmaceutical practice as described, for example, in Remington'sPharmaceutical Sciences (Mack Pub. Co., Easton, Pa., 1980), thedisclosures of which are hereby incorporated herein by reference, intheir entirety.

Compounds of the present invention, preferably compounds of formula Iaor formula IIIa, may be administered to a mammalian host in a variety offorms adapted to the chosen route of administration, e.g., orally orparenterally. Parenteral administration in this respect includesadministration by the following routes: intravenous, intramuscular,subcutaneous, intraocular, intrasynovial, transepithelial includingtransdermal, ophthalmic, sublingual and buccal; topically includingophthalmic, dermal, ocular, rectal and nasal inhalation viainsufflation, aerosol, and rectal systemic.

The active compound may be orally administered, for example, with aninert diluent or with an assimilable edible carrier, or it may beenclosed in hard or soft shell gelatin capsules, or it may be compressedinto tablets, or it may be incorporated directly with the food of thediet. For oral therapeutic administration, the active compound may beincorporated with excipient and used in the form of ingestible tablets,buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers,and the like. The amount of active compound(s) in such therapeuticallyuseful compositions is preferably such that a suitable dosage will beobtained. Preferred compositions or preparations according to thepresent invention may be prepared so that an oral dosage unit formcontains from about 0.1 to about 1000 mg of active compound, and allcombinations and subcombinations of dosage ranges and specific dosageamounts therein.

The tablets, troches, pills, capsules and the like may also contain oneor more of the following: a binder, such as gum tragacanth, acacia, cornstarch, or gelatin; an excipient, such as dicalcium phosphate; adisintegrating agent, such as corn starch, potato starch, alginic acid,and the like; a lubricant, such as magnesium stearate; a sweeteningagent such as sucrose, lactose or saccharin; or a flavoring agent, suchas peppermint, oil of wintergreen, or cherry flavoring. When the dosageunit form is a capsule, it may contain, in addition to materials of theabove type, a liquid carrier. Various other materials may be present ascoatings or to otherwise modify the physical form of the dosage unit.For instance, tablets, pills, or capsules may be coated with shellac,sugar or both. A syrup or elixir may contain the active compound,sucrose as a sweetening agent, methyl and propylparabens aspreservatives, and/or a dye and flavoring, such as cherry or orangeflavor. Of course, any material used in preparing any dosage unit formis preferably pharmaceutically pure and substantially non-toxic in theamounts employed. In addition, the active compound may be incorporatedinto sustained-release preparations and formulations.

The active compound may also be administered parenterally orintraperitoneally. Solutions of the active compounds as free bases orpharmacologically acceptable salts can be prepared in water suitablymixed with a surfactant, such as hydroxypropylcellulose. A dispersioncan also be prepared in glycerol, liquid polyethylene glycols, andmixtures thereof and in oils. Under ordinary conditions of storage anduse, these preparations may contain a preservative to prevent the growthof microorganisms.

The pharmaceutical forms suitable for injectable use include, forexample, sterile aqueous solutions or dispersions and sterile powdersfor the extemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form is preferably sterile and fluid toprovide easy syringability. It is preferably stable under the conditionsof manufacture and storage and is preferably preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier may be a solvent or dispersion medium containing, for example,water, ethanol, polyol (for example, glycerol, propylene glycol, liquidpolyethylene glycol, and the like), suitable mixtures thereof, andvegetable oils. The proper fluidity can be maintained, for example, bythe use of a coating, such as lecithin, by the maintenance of therequired particle size in the case of a dispersion, and by the use ofsurfactants. The prevention of the action of microorganisms may beachieved by various antibacterial and antifungal agents, for example,parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.In many cases, it will be preferable to include isotonic agents, forexample, sugars, or sodium chloride. Prolonged absorption of theinjectable compositions may be achieved by the use of agents delayingabsorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions may be prepared by incorporating the activecompounds in the required amounts, in the appropriate solvent, withvarious of the other ingredients enumerated above, as required, followedby filtered sterilization. Generally, dispersions may be prepared byincorporating the sterilized active ingredient into a sterile vehiclewhich contains the basic dispersion medium and the required otheringredients from those enumerated above. In the case of sterile powdersfor the preparation of sterile injectable solutions, the preferredmethods of preparation may include vacuum drying and the freeze dryingtechnique that yields a powder of the active ingredient, plus anyadditional desired ingredient from the previously sterile-filteredsolution thereof.

The therapeutic compounds of this invention may be administered to apatient alone or in combination with a pharmaceutically acceptablecarrier. The relative proportions of active ingredient and carrier maybe determined, for example, by the solubility and chemical nature of thecompounds, chosen route of administration, and standard pharmaceuticalpractice.

The dosage of the compounds of the present invention that will be mostsuitable for prophylaxis or treatment will vary with the form ofadministration, the particular compound chosen and the physiologicalcharacteristics of the particular patient under treatment. Generally,small dosages may be used initially and, if necessary, increased bysmall increments until the desired effect under the circumstances isreached. Generally speaking, oral administration may require higherdosages. Although the proper dosage of the products of this inventionwill be readily ascertainable by one skilled in the art, once armed withthe present disclosure, by way of general guidance, for example,typically a daily dosage of the compound of the invention, preferably acompound of formula Ia or formula IIIa, as described herein, may rangefrom about 0.001 to about 100 milligrams (and all combinations andsubcombinations of ranges and specific dosage amounts therein), perkilogram of patient body weight. Preferably, the daily dosage may beabout 0.01 to about 10 milligrams of the compound of the invention,preferably a compound of formula Ia or formula IIIa per kilogram ofpatient body weight. Even more preferably, the daily dosage may be about0.1 milligrams of the compound of the invention, preferably a compoundof formula Ia or formula IIIa per kilogram of patient body weight. Withregard to a typical dosage form of this type, such as a tablet, thecompounds of the invention, preferably a compound of formula Ia orformula IIIa, generally may be present in an amount of about 0.1 toabout 4 milligrams.

The combination products of this invention, such as pharmaceuticalcompositions comprising one or more opioids in combination with one ormore compounds of the invention, preferably one or more compounds offormula Ia or formula IIIa, as described herein, or one or morepharmaceutically acceptable salts thereof, may be in any dosage form,such as those described herein, and can also be administered in variousways, as described herein. In a preferred embodiment, the combinationproducts of the invention are formulated together, in a single dosageform (that is, combined together in one capsule, tablet, powder, orliquid, etc.). When the combination products are not formulated togetherin a single dosage form, the opioid compound and the compound of theinvention, preferably a compound of formula Ia or formula IIIa, may beadministered at the same time (that is, together), or in any order. Whennot administered at the same time, preferably the administration of anopioid and the compound of the invention, preferably a compound offormula Ia or formula IIIa, occur less than about one hour apart, morepreferably less than about 30 minutes apart, even more preferably lessthan about 15 minutes apart, and still more preferably less than about 5minutes apart. Preferably, administration of the combination products ofthe invention is oral, although other routes of administration, asdescribed above, are contemplated to be within the scope of the presentinvention. Although it is preferable that the opioid and the compound ofthe invention, preferably a compound of formula Ia or formula IIIa, areboth administered in the same fashion (that is, for example, bothorally), if desired, they may each be administered in different fashions(that is, for example, one component of the combination product may beadministered orally, and another component may be administeredintravenously). The dosage of the combination products of the inventionmay vary depending upon various factors such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration, the age, health and weight of the recipient, the natureand extent of the symptoms, the kind of concurrent treatment, thefrequency of treatment, and the effect desired.

Although the proper dosage of the combination products of this inventionwill be readily ascertainable by one skilled in the art, once armed withthe present disclosure, by way of general guidance, where an opioidcompound is combined with a compound of the invention, preferably acompound of formula Ia or formula IIIa, as described herein, forexample, typically a daily dosage may range from about 0.01 to about 100milligrams of the opioid (and all combinations and subcombinations ofranges and specific dosage amounts therein) and about 0.001 to about 100milligrams of the compound of the invention, preferably a compound offormula Ia or formula IIIa, (and all combinations and subcombinations ofranges and specific dosage amounts therein), per kilogram of patientbody weight. Preferably, a daily dosage may be about 0.1 to about 10milligrams of the opioid and about 0.01 to about 10 milligrams of thecompound of the invention, preferably a compound of formula Ia orformula IIIa, per kilogram of patient body weight. Even more preferably,the daily dosage may be about 1.0 milligrams of the opioid and about 0.1milligrams of the compound of the invention, preferably a compound offormula Ia or formula IIIa, per kilogram of patient body weight. Withregard to a typical dosage form of this type of combination product,such as a tablet, the opioid compound (e.g., morphine) generally may bepresent in an amount of about 15 to about 200 milligrams, and thecompound of the invention, preferably a compound of formula Ia orformula IIIa, in an amount of about 0.1 to about 4 milligrams.

Particularly when provided as a single dosage form, the potential existsfor a chemical interaction between the combined active ingredients (forexample, an opioid and a compound of the invention, preferably acompound of formula Ia or formula IIIa). For this reason, the preferreddosage forms of the combination products of this invention areformulated such that although the active ingredients are combined in asingle dosage form, the physical contact between the active ingredientsis minimized (that is, reduced).

In order to minimize contact, one embodiment of this invention where theproduct is orally administered provides for a combination productwherein one active ingredient is enteric coated. By enteric coating oneor more of the active ingredients, it is possible not only to minimizethe contact between the combined active ingredients, but also, it ispossible to control the release of one of these components in thegastrointestinal tract such that one of these components is not releasedin the stomach but rather is released in the intestines. Anotherembodiment of this invention where oral administration is desiredprovides for a combination product wherein one of the active ingredientsis coated with a sustained-release material that effects asustained-release throughout the gastrointestinal tract and also servesto minimize physical contact between the combined active ingredients.Furthermore, the sustained-released component can be additionallyenteric coated such that the release of this component occurs only inthe intestine. Still another approach would involve the formulation of acombination product in which the one component is coated with asustained and/or enteric release polymer, and the other component isalso coated with a polymer such as a low-viscosity grade ofhydroxypropyl methylcellulose (HPMC) or other appropriate materials asknown in the art, in order to further separate the active components.The polymer coating serves to form an additional barrier to interactionwith the other component.

Dosage forms of the combination products of the present inventionwherein one active ingredient is enteric coated can be in the form oftablets such that the enteric coated component and the other activeingredient are blended together and then compressed into a tablet orsuch that the enteric coated component is compressed into one tabletlayer and the other active ingredient is compressed into an additionallayer. Optionally, in order to further separate the two layers, one ormore placebo layers may be present such that the placebo layer isbetween the layers of active ingredients. In addition, dosage forms ofthe present invention can be in the form of capsules wherein one activeingredient is compressed into a tablet or in the form of a plurality ofmicrotablets, particles, granules or non-perils, which are then entericcoated. These enteric coated microtablets, particles, granules ornon-perils are then placed into a capsule or compressed into a capsulealong with a granulation of the other active ingredient.

These as well as other ways of minimizing contact between the componentsof combination products of the present invention, whether administeredin a single dosage form or administered in separate forms but at thesame time by the same manner, will be readily apparent to those skilledin the art, once armed with the present disclosure.

Pharmaceutical kits useful in, for example, the treatment of pain, whichcomprise a therapeutically effective amount of an opioid along with atherapeutically effective amount of one or more quinolizidine andoctahydropyridopyrazine compounds of the invention, in one or moresterile containers, are also within the ambit of the present invention.Sterilization of the container may be carried out using conventionalsterilization methodology well known to those skilled in the art. Thesterile containers of materials may comprise separate containers, or oneor more multi-part containers, as exemplified by the Univial™ two-partcontainer (available from Abbott Labs, Chicago, Ill.), as desired. Theopioid compound and the compound of the invention, preferably a compoundof formula Ia or formula IIIa, may be separate, or combined into asingle dosage form as described above. Such kits may further include, ifdesired, one or more of various conventional pharmaceutical kitcomponents, such as for example, one or more pharmaceutically acceptablecarriers, additional vials for mixing the components, etc., as will bereadily apparent to those skilled in the art. Instructions, either asinserts or as labels, indicating quantities of the components to beadministered, guidelines for administration, and/or guidelines formixing the components, may also be included in the kit.

It will be further appreciated that the amount of the compound, or anactive salt or derivative thereof, required for use in treatment willvary not only with the particular salt selected but also with the routeof administration, the nature of the condition being treated and the ageand condition of the patient and will be ultimately at the discretion ofthe attendant physician or clinician.

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations; such as multiple inhalations from an insufflator or byapplication of a plurality of drops into the eye.

The dose may also be provided by controlled release of the compound, bytechniques well known to those in the art.

The compounds of the present invention may be used in methods to bindopioid receptors, including μ, κ, and/or δ opioid receptors. Suchbinding may be accomplished by contacting the receptor with an effectiveamount of the compound of the invention. Preferably, the contacting stepconducted in an aqueous medium, preferably at physiologically relevantionic strength, pH, and the like.

In certain preferred embodiments, the compounds of the present inventionbind μ and/or κ opioid receptors, or combinations thereof. The opioidreceptors may be located in the central nervous system or locatedperipherally to the central nervous system or in both locations.

In certain other preferred embodiments, the compounds of the presentinvention bind κ opioid receptors.

In preferred embodiments of the methods of the invention, the compoundsantagonize the activity of the opioid receptors. In other preferredembodiments, the compounds prevent or treat a condition or diseasecaused by an opioid (either endogenous or exogenous). In certainembodiments of the method, particularly where the opioid are exogenous,the compounds of the invention preferably do not substantially cross theblood-brain barrier.

The compounds of the present invention may be used in methods toantagonize μ, κ, and/or δ opioid receptors or any combinations orsubcombinations of those opioid receptors, particularly whereundesirable symptoms or conditions are side effects of administeringexogenous opioids. Furthermore, the compounds of the invention may beused as to treat patients having disease states that are ameliorated bybinding opioid receptors or in any treatment wherein temporarysuppression of the μ, κ, or both types of opioid receptor system isdesired.

Such symptoms, conditions or diseases include the complete or partialantagonism of opioid-induced sedation, confusion, respiratorydepression, euphoria, dysphoria, hallucinations, pruritus (itching),increased biliary tone, increased biliary colic, and urinary retention,ileus, emesis, and addiction liability; prevention or treatment ofopioid and cocaine dependence; rapid opioid detoxification; treatment ofalcoholism; treatment of alcoholic coma; detection of opioid use orabuse (pupil test); treatment of eating disorders; treatment of obesity;treatment of post-concussional syndrome; adjunctive therapy in septic,hypovolemic or endotoxin-induced shock; potentiation of opioid analgesia(especially at ultra-low doses); reversal or prevention of opioidtolerance and physical dependence (especially at ultra-low doses);treatment of psychosis (especially wherein the symptoms are associatedwith schizophrenia, schizophreniform disorder, schizoaffective disorder,unipolar disorder, bipolar disorder, psychotic depression, Alzheimer'sdisease, Parkinson's disease, compulsive disorders, and otherpsychiatric or neurologic disorders with psychosis as symptoms);treatment of dyskinesia, treatment of autism; treatment of the endocrinesystem (including increased release of leutinizing hormone, treatment ofinfertility, increasing number of multiple births in animal husbandry,and male and female sexual behavior); treatment of the immune system andcancers associated with binding of the opioid receptors; treatment ofanxiolysis; treatment of diuresis; treatment and regulation of bloodpressure; treatment of tinnitus or impaired hearing; treatment ofepilepsy; treatment of cachexia; treatment of general cognitivedysfunctions; and treatment of kleptomania.

The compounds of the present invention may also be used as cytostaticagents, as antimigraine agents, as immunomodulators, asimmunosuppressives, as antiarthritic agents, as antiallergic agents, asvirucides, to treat diarrhea, antipsychotics, as antischizophrenics, asantidepressants, as uropathic agents, as antitussives, as antiaddictiveagents, as anti-smoking agents, to treat alcoholism, as hypotensiveagents, to treat and/or prevent paralysis resulting from traumaticischemia, general neuroprotection against ischemic trauma, as adjunctsto nerve growth factor treatment of hyperalgesia and nerve grafts, asanti-diuretics, as stimulants, as anti-convulsants, or to treat obesity.Additionally, the present compounds may be used in the treatment ofParkinson's disease as an adjunct to L-dopa for treatment dyskinesiaassociated with the L-dopa treatment.

In certain preferred embodiments, the compounds of the invention may beused in methods for preventing or treating gastrointestinal dysfunction,including, but not limited to, irritable bowel syndrome, opioid-boweldysfunction, colitis, post-operative and opioid-induced emesis (nauseaand vomiting), decreased gastric motility and emptying, inhibition ofsmall and/or large intestinal propulsion, increased amplitude ofnon-propulsive segmental contractions, constriction of sphincter ofOddi, increased anal sphincter tone, impaired reflex relaxation withrectal distention, diminished gastric, biliary, pancreatic or intestinalsecretions, increased absorption of water from bowel contents,gastro-esophageal reflux, gastroparesis, cramping, bloating, abdominalor epigastric pain and discomfort, constipation, and delayed absorptionof orally administered medications or nutritive substances.

Methods of Preparation

The examples listed in Table 1 were prepared according to Schemes 1-9.The synthesis of compound 1 is outlined in Scheme 1. Condensation of 1.1with di-tert butyldicarbonate 1.2 affordedN-boc-(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-piperidine 1.3.Alkylation of 1.3 with benzyl bromide 1.4 in the presence of potassiumcarbonate gave the benzyl ether derivative 1.5. Treatment of 1.5 withanhydrous hydrogen chloride in dioxane at room temperature followed bytreatment with aqueous sodium bicarbonate solution yielded the free base1.6. Oxidation of 1.6 using sodium tungstate and hydrogen peroxidesolution afforded the regioisomers 1.7a/b. Alkylation of 1.7a/b withallylmagnesium chloride 1.8 gave a mixture of regio- and stereoisomers(1.9, 1.10, 1.11 and 1.12) that were separated by column chromatography.Sonication of 1.9 in acetic acid/water in the presence of zinc dustprovided the piperidine derivative 1.13. Peptidic type coupling of 1.13with benzoylformic acid 1.14 in the presence ofO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) gave 1.15. Condensation of 1.15 with 1.16 under standard Wittigconditions provided 1.17. Compound 1.19 was synthesized by refluxing asolution of 1.17 in dichloromethane in the presence of a catalyticamount of(1,3-Bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(phenylmethylene)-(tricyclohexylphosphine)ruthenium,1.18, (Grubbs catalyst, 2^(nd) generation) in a ring closure metathesis(RCM) reaction. Hydrogenation of 1.19 using palladium 10 wt. %. (drybasis) on activated carbon gave a mixture of 1.20 and 1.21, separated bycolumn chromatography. Reduction of 1.20 with borane-dimethylsulfidecomplex provided the target compound 1.

The syntheses of compounds 2A-2F are outlined in Scheme 2. Compound 1.2was reacted with tert-butyldimethylchlorosilane 2.1 to give compound2.2. Treatment of a solution of 2.2 in diethyl ether at −78° C. withsec-butyl lithium, followed by addition of carbon dioxide gas yieldedcarboxylic acid derivative 2.3. The reaction was found to be highlyregio- and stereospecific. Peptidic type coupling of 2.3 with glycinemethyl ester hydrochloride 2.4 provided 2.5. Conversion of 2.5 to 2.6was achieved in two steps, i.e.: (a) cleavage of the Boc and TBDMSprotecting groups of 2.5 under acidic conditions; (b) cyclization inmethanol in the presence of triethylamine. Reduction of the lactam 2.6with borane-dimethylsulfide complex provided compound 2.7. Condensationof 2.7 with phenylacetyl chloride 2.8 in the presence of triethylamineprovided compound 2A. Reduction of compound 2A using borane-methylsulfide complex afforded compound 2B. Condensation of 2.7 with benzoylchloride 2.9 provided compound 2C. Reduction of compound 2C usingborane-dimethylsulfide complex afforded compound 2D. Condensation ofcompound 2.7 with di-tert-butyldicarbonate 1.2 gave compound 2.10 whichreacted with benzyl bromide 1.4 in the presence of potassium carbonateto afford compound 2.11. Boc deprotection of 2.11 using an anhydroussolution of hydrogen chloride in dioxane, followed by treatment with asaturated solution of sodium bicarbonate gave the free base 2.12.Condensation of compound 2.12 with benzene sulfonyl chloride 2.13afforded the sulfonamide 2.14. Removal of the benzyl protecting group of2.14 under hydrogenation conditions provided compound 2E. Condensationof compound 2.12 with potassium phenyltrifluoroborate 2.15 in thepresence of copper (II) acetate and triethylamine gave compound 2.16.Hydrogenation of 2.16 yielded compound 2F.

The syntheses of compounds 3A-3G are outlined in Scheme 3. Peptidic typecoupling of 2.3 with L-phenylglycine methyl ester hydrochloride 3.1provided 3.2. Treatment of 3.2 with anhydrous hydrogen chloride indioxane in refluxing methanol, followed by treatment with a saturatedsolution of sodium bicarbonate gave 3.3 as the free base. Intramolecularcyclization of 3.3 provided the lactam 3.4. Reduction of 3.4 withborane-dimethylsulfide complex gave compound 3A. Condensation ofcompound 3A with formaldehyde 3.5 under reductive amination conditionsusing sodium cyanoborohydride as the reducing agent provided compound3B. Alkylation of compound 3A with tert-butyl bromoacetate 3.6 in thepresence of potassium carbonate afforded compound 3.7, which washydrolyzed under acidic conditions to give compound 3C. The 1,4-additionof compound 3A with tert-butyl acrylate 3.8 afforded compound 3.9, whichwas hydrolyzed under acidic conditions to give compound 3D. Condensationof compound 3A with benzaldehyde 3.10 under reductive aminationconditions using borane-pyridine complex as the reducing agent providedcompound 3E. Condensation of 3E with N-phenyltrifluoromethanesulfonimide3.11 gave the triflate 3.12. Palladium catalyzed carbonylation of thetriflate 3.12 using palladium (II) acetate and1,1′-bis(diphenylphosphino)ferrocene (dppf) in a methanol,dimethylsulfoxide mixture provided the methyl ester 3.13 which washydrolyzed under basic conditions to provide the carboxylic acid 3.14.Peptidic type coupling of 3.14 with ammonium chloride afforded 3F.Hydrogenation of 3F yielded 3G.

The synthesis of compound 4 is outlined in Scheme 4. Peptidic typecoupling of 2.3 with L-phenylalanine methyl ester hydrochloride 4.1provided 4.2. Treatment of 4.2 with anhydrous hydrogen chloride indioxane in refluxing methanol, followed by treatment with a saturatedsolution of sodium bicarbonate gave 4.3 as the free base. Cyclization of4.3 to 4.4 was achieved by refluxing a solution of 4.3 in toluene.Reduction of 4.4 with borane-dimethylsulfide complex gave compound 4.

The synthesis of compound 5 is described in Scheme 5. Peptidic typecoupling of 2.3 with D-phenylalanine methyl ester hydrochloride 5.1provided 5.2. Treatment of 5.2 with anhydrous hydrogen chloride indioxane in refluxing methanol, followed by treatment with a saturatedsolution of sodium bicarbonate gave 5.3 as the free base. Cyclization of5.3 to 5.4 was achieved by refluxing a solution of 5.3 in toluene.Reduction of 5.4 with borane-dimethylsulfide complex gave compound 5.

The synthesis of compound 6 is described in Scheme 6. Peptidic typecoupling of 2.3 with L-cyclohexylglycine methyl ester hydrochloride 6.1provided 6.2. Treatment of 6.2 with anhydrous hydrogen chloride indioxane in refluxing methanol, followed by treatment with a saturatedsolution of sodium bicarbonate gave 6.3 as the free base. Cyclization of6.3 to 6.4 was achieved by refluxing a solution of 6.3 in o-xylene.Reduction of 6.4 with borane-dimethylsulfide complex gave compound 6.

The synthesis of compound 7 is described in Scheme 7. Peptidic typecoupling of 2.3 with N-benzyl-beta-alanine ethyl ester 7.1 provided 7.2.Treatment of 7.2 with anhydrous hydrogen chloride in dioxane andethanol, followed by treatment with a saturated solution of sodiumbicarbonate gave 7.3 as the free base. Cyclization of 7.3 to 7.4 wasachieved by refluxing a solution of 7.3 in o-xylene. Reduction of 7.4with borane-dimethylsulfide complex gave compound 7.

The syntheses of compounds 8A-8AQ are described in Scheme 8.Condensation of compound 2.7 with aldehydes 8.1a-8.1aq under reductiveamination conditions using polymer bound cyanoborohydride as thereducing agent furnished compounds 8A-8AQ respectively. Compounds 8A-8AQwere purified by liquid chromatography.

The syntheses of compounds 9A-9B are outlined in Scheme 9. Peptidic typecoupling of 2.3 with 9.1 provided 9.2. Treatment of 9.2 with anhydroushydrogen chloride in dioxane, followed by treatment with a saturatedsolution of sodium bicarbonate gave 9.3 as the free base. Intramolecularcyclization of 9.3 provided the lactam 9.4. Reduction of 9.4 withborane-dimethylsulfide complex gave compound 9.5. Peptidic type couplingof 9.5 with 3-(4-hydroxyphenyl)propionic acid 9.6 in the presence ofO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) gave 9A. Peptidic type coupling of 9.5 withN-t-butyloxycarbonyl-7-hydroxy-D-1,2,3,4-tetrahydroisoquinoline-3-carboxylicacid 9.7 in the presence ofO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) gave compound 9.8, which was converted to 9B under acidicconditions.

The present invention will now be illustrated by reference to thefollowing specific, non-limiting examples. Those skilled in the art oforganic synthesis may be aware of still other synthetic routes to theinvention compounds. The reagents and intermediates used herein areeither commercially available or prepared according to standardliterature procedures.

EXAMPLES

Materials: All chemicals were reagent grade, purchased from AldrichChemical Company, Milwaukee, Wis. or Lancaster Synthesis, Windham, N.H.,and used without further purification. General: Thin-layerchromatography (TLC) was performed on silica gel 6F glass backed plates(250 microns) from Analtech and visualized by UV 254 irradiation andiodine. Flash chromatography was conducted using the ISCO CombiFlashwith RediSep silica gel cartridges (4 g, 12 g, 40 g, 120 g).Chromatographic elution solvent systems are reported as volume:volumeratios. All ¹H NMR spectra were recorded at ambient temperature on aBruker-400 MHz spectrometer. They are reported in ppm on the δ scale,from TMS. LC-MS data were obtained using a Thermo-Finnigan Surveyor HPLCand a Thermo-Finnigan AQA MS using either positive or negativeelectrospray ionization. Program (positive) Solvent A: 10 mM ammoniumacetate, pH 4.5, 1% acetonitrile; solvent B: acetonitrile; column:Michrom Bioresources Magic C18 Macro Bullet, detector: PDA λ=220-300 nm.Gradient: 96% A-100% B in 3.2 minutes, hold 100% B for 0.4 minutes.Program (negative) Solvent A: 1 mM ammonium acetate, pH 4.5, 1%acetonitrile; solvent B: acetonitrile; column: Michrom BioresourcesMagic C18 Macro Bullet, detector: PDA λ=220-300 nm. Gradient: 96% A-100%B in 3.2 minutes, hold 100% B for 0.4 minutes.

Example 1 Preparation of 1.3

To a stirred solution of 1.1 (30 g, 146 mmol) in tetrahydrofuran (150mL) under nitrogen at 0° C., was added a solution of 1.2 (35 g, 160mmol) and triethylamine (24.45 mL, 175 mmol) in tetrahydrofuran (150 mL)over 1 hour. The solution was stirred at room temperature for 18 hours.The reaction mixture was concentrated under reduced pressure and theresidue dissolved in ethyl acetate (300 mL). The solution was thenwashed with 0.5M aqueous solution of hydrochloric acid (2×60 mL) anddried over sodium sulfate. The reaction mixture was concentrated underreduced pressure and used in the next step without further purification.Yield: 100% ¹H NMR (400 MHz, CDCl₃) δ: 0.64 (d, J=7 Hz, 3H), 1.35 (s,3H), 1.47 (s, 9H), 1.53 (m, 1H), 1.97 (br s, 1H), 2.19 (dt, J=13 Hz and5 Hz, 1H), 3.05 (br s, 1H), 3.30 (br s, 1H), 3.82 (br s, 1H), 4.10 (brs, 0.5H), 4.24 (br s, 0.5H), 6.23 (br s, 1H), 6.68 (m, 1H), 6.78 (m,2H), 7.17 (t, J=8 Hz 1H)

Mass Spectral Analysis, m/z ESI 306 (M+H⁺)

Preparation of 1.5

To a stirred solution of 1.3 (44.63 g, 146 mmol) inN,N-dimethylformamide (450 mL) was added 1.4 (20.8 mL, 175 mmol) andpotassium carbonate (60.50 g, 438 mmol) and the reaction stirred at roomtemperature for 18 hours. The reaction mixture was then poured intowater (300 mL) and extracted with hexanes. The combined organics werewashed with water, brine and dried over sodium sulfate. The mixture wasfiltered and the filtrate concentrated under reduced pressure. Thedesired product was used for the next step without further purification.Yield: 100% ¹H NMR (400 MHz, CDCl₃) δ: 0.62 (d, J=7 Hz, 3H), 1.35 (s,3H), 1.46 (s, 9H), 1.56 (m, 1H), 1.96 (br s, 1H), 2.18 (dt, J=13 Hz and5 Hz, 1H), 3.02 (br s, 1H), 3.27 (br s, 1H), 3.82 (br s, 1H), 4.18 (brs, 1H), 5.05 (s, 2H), 6.80 (m, 1H), 6.86 (m, 2H), 7.24 (t, J=8 Hz 1H),7.32 (m, 1H), 7.38 (m, 2H), 7.44 (m, 2H)

Mass Spectral Analysis, m/z ESI 396 (M+H⁺)

Preparation of 1.6

To a stirred solution of 1.5 (57.80 g, 146 mmol) in methanol (300 mL)was added a 4M anhydrous solution of hydrogen chloride in dioxane (200mL) and the reaction mixture was stirred at room temperature for 18hours. The solvents were then removed under reduced pressure and theresidue stirred with saturated sodium bicarbonate solution (400 mL),ethyl acetate (200 mL) and dichloromethane (200 mL) for 4 hours. Thelayers were separated and the organic layer washed with brine and driedover sodium sulfate. The reaction mixture was filtered and the filtrateconcentrated under reduced pressure. The desired product used for thenext step without further purification.

Yield: 96% ¹H NMR (400 MHz, CDCl₃) δ: 0.73 (d, J=7 Hz, 3H), 1.37 (s,3H), 1.56 (d, J=14 Hz, 1H), 1.93 (m, 1H), 2.15 (dt, J=13 Hz and 5 Hz,1H), 2.76 (d, J=12 Hz, 1H), 3.01 (dt, J=12 Hz and 3 Hz, 1H), 3.09 (d,J=13 Hz, 1H), 3.26 (dd, J=13 Hz and 3 Hz, 1H), 5.06 (s, 2H), 6.80 (m,1H), 6.88 (m, 2H), 7.24 (t, J=8 Hz 1H), 7.33 (m, 1H), 7.39 (m, 2H), 7.45(m, 2H) Mass Spectral Analysis, m/z ESI 296 (M+H⁺)

Preparation of 1.7a-b

To a stirred solution of 1.6 (29.35 g, 99.49 mmol) in methanol (200 mL)and dichloromethane (200 mL) was added a solution of sodium tungstate(1.50 g, 3.98 mmol) in water (50 mL). To this was then added hydrogenperoxide (35 mL, 298.47 mmol) and the reaction was stirred at roomtemperature for 18 hours. The mixture was then poured into saturatedammonium chloride solution (500 mL) and extracted with dichloromethane.The combined organic fractions were dried over sodium sulfate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography (eluent: dichloromethane/methanol mixtures ofincreasing polarity). Note: 1.7a and 1.7b could not be separated bycolumn chromatography. Yield: 68% ¹H NMR (400 MHz, CDCl₃) (1.7a/1.7b) δ:0.75 and 0.83 (d, J=7 Hz, 3H), 1.39 and 1.43 (s, 3H), 2.33 (m, 1H), 2.58(dd, J=20 Hz and 2 Hz, 1H), 2.92 (d, J=20 Hz, 1H), 3.41 (dd, J=15 Hz and3 Hz, 1H), 3.94 (d, J=15 Hz, 2H), 5.06 (s, 2H), 6.82-6.89, (m, 3H),7.26-7.43 (m, 6H)

Mass Spectral Analysis, m/z ESI 310 (M+H⁺)

Preparation of 1.9

An oven dried flask was charged with a solution of 1.7a-b (25 g, 80.91mmol) in anhydrous tetrahydrofuran (500 mL) and the solution, under anitrogen atmosphere, was cooled in an ice bath. To the mixture was thenadded, dropwise, a 2M solution of 1.8 in tetrahydrofuran (122 mL, 244mmol). Once the addition was complete the ice bath was removed and thereaction was stirred at room temperature for 1.5 hours. The reactionmixture was poured into a mixture of saturated ammonium chloridesolution (250 mL) and saturated sodium bicarbonate solution (250 mL).The mixture was extracted with ethyl acetate and the combined organicextracts were washed with brine and dried over sodium sulfate. Themixture was filtered and the filtrate was concentrated under reducedpressure. The crude material was purified by column chromatography(eluent: hexane/ethyl acetate mixtures of increasing polarity). Yield:8% ¹H NMR (400 MHz, CDCl₃) δ: 0.73 (d, J=7 Hz, 3H), 1.36 (s, 3H), 1.41(m, 0.5H), 1.58 (m, 0.5H), 1.78 (d, J=14 Hz, 1H), 1.97 (t, J=13 Hz,0.5H), 2.06-2.13 (br m, 1.5H), 2.24 (m, 0.5H), 2.78-2.82, (br m, 2H),3.08 (d, J=10 Hz 0.5H), 3.18 (d, J=11 Hz, 0.5H), 3.65 (t, J=6 Hz, 0.5H),5.05 (s, 2H), 5.08-5.17 (m, 2H), 5.88 (m, 1H), 6.13 (br s, 1H), 6.79 (d,J=8 Hz, 1H), 6.84 (br d, J=7 Hz, 2H), 7.23 (t, J=8 Hz, 1H), 7.33-7.45(m, 5H)

Mass Spectral Analysis, m/z ESI 352 (M+H⁺)

Preparation of 1.13

To a solution of 1.9 (1.62 g, 4.62 mmol) in acetic acid/water (1:1, 30mL) was added zinc dust (1.50 g, 23.08 mmol) and the reaction mixturewas sonicated for 2 hours. The reaction mixture was then filteredthrough celite and the filtrate was basified with saturated sodiumbicarbonate solution. The aqueous was extracted with ethyl acetate andthe organic extracts were washed with brine, dried over sodium sulfateand concentrated under reduced pressure. The desired product was usedfor the next step without further purification. Yield: 92% ¹H NMR (400MHz, CDCl₃) δ: 0.67 (d, J=7 Hz, 3H), 1.36 (s, 3H), 1.58 (d, J=13 Hz,1H), 1.74 (t, J=12 Hz, 2H), 1.89 (m, 1H), 2.22 (m, 2H), 2.76 (d, J=13Hz, 1H), 2.94 (m, 1H), 3.29 (dd, J=13 Hz and 3 Hz, 1H), 5.04 (s, 2H),5.12 (m, 2H), 5.86 (m, 1H), 6.79 (d, J=7 Hz, 1H), 6.89 (m, 2H), 7.23 (t,J=8 Hz, 1H), 7.31 (t, J=8 Hz, 1H), 7.35 (t, J=7 Hz, 2H), 7.44 (t, J=13Hz, 2H) Mass Spectral Analysis, m/z ESI 336 (M+H⁺)

Preparation of 1.15

To a stirred solution of 1.13 (1.5 g, 4.48 mmol) in acetonitrile (20 mL)under a nitrogen atmosphere was added, sequentially,diisopropylethylamine (2.3 mL, 13.44 mmol), 1.14 (0.81 g, 5.37 mmol) andO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) (2.16 g, 6.72 mmol). The reaction mixture was stirred at roomtemperature for 3 hours, poured into saturated ammonium chloridesolution and extracted with ethyl acetate. The organic extracts werewashed with brine, dried over sodium sulfate and concentrated underreduced pressure. The crude material was purified by columnchromatography (eluent: hexane/ethyl acetate mixtures of increasingpolarity). Yield: 26%

¹H NMR (400 MHz, CDCl₃) δ: 0.40 (d, J=7 Hz, 3H), 1.39 (s, 1H), 1.44 (s,3H), 1.93 (m, 1H), 2.08 (m, 1H), 2.46 (m, 2H), 2.92 (dd, J=11 Hz and 3Hz, 1H), 3.40 (dd, J=15 Hz and 7 Hz, 1H), 4.58 (m, 1H), 5.06 (s, 2H),5.17 (m, 2H), 5.92 (m, 1H), 6.81 (dd, J=8 Hz and 3 Hz, 1H), 6.87 (m,2H), 7.22 (t, J=8 Hz, 1H), 7.33 (t, J=7 Hz, 1H), 7.38 (t, J=7 Hz, 2H),7.44 (d, J=7 Hz, 2H), 7.52 (t, J=8 Hz, 2H), 7.65 (t, J=8 Hz, 1H), 7.99(d, J=7 Hz, 2H)

Mass Spectral Analysis, m/z ESI 468 (M+H⁺)

Preparation of 1.17

To a suspension of methyl phosphonium bromide (0.83 g, 2.31 mmol) inanhydrous tetrahydrofuran (10 mL) under a nitrogen atmosphere, was addedpotassium tert-butoxide (0.29 g, 2.55 mmol) in one portion. The brightyellow mixture was stirred at room temperature for 30 minutes to give1.16. The solution of 1.16 was transferred to a solution of 1.15 (0.54g, 1.16 mmol) in anhydrous benzene (10 mL). The reaction mixture wasthen heated to reflux for 2 hours and concentrated under reducedpressure. The crude product was purified by column chromatography(eluent: hexane/ethyl acetate mixtures of increasing polarity). Yield:71% ¹H NMR (400 MHz, CDCl₃) δ: 0.34 (br s, 3H), 1.34 (s, 3H), 1.73-1.84(m, 2H), 1.99 (d, J=14 Hz, 1H), 2.38-2.43 (m, 2H), 2.78 (t, J=13 Hz,1H), 3.65 (br s, 1H), 4.55 (br s, 1H), 5.04 (s, 2H), 5.07 (m, 2H), 5.37(s, 1H), 5.71 (s, 1H), 5.84 (br s, 1H), 6.79 (dd, J=8 Hz and 2 Hz, 1H),6.86 (s, 2H), 7.20 (t, J=8 Hz, 1H), 7.31-7.38 (m, 6H), 7.42 (d, J=13 Hz,2H), 7.48 (d, J=8 Hz, 2H) Mass Spectral Analysis, m/z ESI 466 (M+H⁺)

Preparation of 1.19

A solution of 1.17 (0.38 g, 0.82 mmol) in anhydrous dichloromethane (20mL) was purged with nitrogen for 20 minutes. The second generationGrubbs catalyst 1.18 (0.035 g, 0.04 mmol) was added to the reactionmixture, which was then heated to reflux for 2 hours. The mixture wasthen concentrated under reduced pressure. The crude product was purifiedby column chromatography (eluent: hexane/ethyl acetate mixtures ofincreasing polarity).

Yield: 95% ¹H NMR (400 MHz, CDCl₃) δ: 0.72 (d, J=7 Hz, 3H), 1.41 (s,3H), 1.56 (s, 1H), 1.83 (dd, J=13 Hz and 3 Hz, 1H), 2.18 (m, 2H), 2.49(m, 1H), 2.61 (t, J=6 Hz, 0.6H), 2.65 (t, J=6 Hz, 0.4H), 3.32 (dd, J=14Hz and 3 Hz, 1H), 3.89 (m, 1H), 4.30 (dd, J=14 Hz and 2 Hz, 1H), 5.07(s, 2H), 6.62 (dd, J=6 Hz and 2 Hz, 1H), 6.83 (dd, J=8 Hz and 2 Hz, 1H),6.91 (m, 2H), 7.26-7.35 (m, 5H), 7.38-7.47 (m, 5H)

Mass Spectral Analysis, m/z ESI 438 (M+H⁺).

Preparation of 1.20

To a solution of 1.19 (0.34 g, 0.77 mmol) in ethanol (20 mL) was added10% palladium on charcoal (0.02 g) and the mixture was stirred at roomtemperature under a hydrogen atmosphere for 16 hours. The mixture wasthen filtered through celite. The celite was washed with ethanol and thefiltrate was evaporated under reduced pressure. The crude product waspurified by column chromatography (eluent: hexane/ethyl acetate mixturesof increasing polarity). Yield: 15% ¹H NMR (400 MHz, CD₃OD) δ: 0.64 (d,J=7 Hz, 3H), 1.47 (s, 3H), 1.80 (d, J=13 Hz, 2H), 2.18 (m, 3H), 3.28(dd, J=13 Hz and 3 Hz, 1H), 3.33 (s, 2H), 3.67 (dd, J=10 Hz and 5 Hz,1H), 3.92 (m, 1H), 4.54 (dd, J=13 Hz and 3 Hz, 1H), 6.63 (dd, J=7 Hz and2 Hz, 1H), 6.77 (s, 1H), 6.81 (d, J=8 Hz, 1H), 7.16 (t, J=8 Hz, 1H),7.23 (m, 3H), 7.32 (t, J=8 Hz, 2H) Mass Spectral Analysis, m/z ESI 350(M+H⁺).

Preparation of 1

To a solution of 1.20 (0.04 g, 0.11 mmol) in anhydrous tetrahydrofuran(10 mL) was added borane-dimethyl sulfide complex (2M solution intetrahydrofuran, 0.11 mL, 0.22 mmol) and the reaction mixture was heatedto reflux under a nitrogen atmosphere for 16 hours. The mixture was thencooled to 0° C. and methanol (10 mL) was added. The reaction mixture wasstirred at 0° C. for 1 hour. A 2M solution of hydrogen chloride indiethyl ether (10 mL) was then added to the mixture, which was heated toreflux for 1 hour. The mixture was concentrated under reduced pressure.The residue was taken up in methanol (10 mL) and the solution wasconcentrated under reduced pressure. This process was repeated 5 times.The residue was then basified with 1N aqueous solution of sodiumhydroxide (5 mL) and the mixture was extracted with CH₂Cl₂/MeOH (9:1)(100 mL). The organic extracts were collected, washed with brine anddried over sodium sulfate. The mixture was filtered and the filtrateconcentrated under reduced pressure. The crude product was purified bycolumn chromatography (eluent: hexane/ethyl acetate mixture ofincreasing polarity) Yield: 78% ¹H NMR (400 MHz, CD₃OD) δ: 0.79 (d, J=7Hz, 3H), 1.38 (s, 3H), 1.57 (m, 1H), 1.67 (m, 2H), 1.83 (m, 1H), 1.98(m, 2H), 2.09 (m, 1H), 2.33 (m, 1H), 2.42 (m, 1H), 2.68 (d, J=7 Hz, 1H),2.92 (m, 3H), 6.59 (dd, J=8 Hz and 2 Hz, 1H), 6.73 (m, 1H), 6.77 (d, J=7Hz, 1H), 7.11 (t, J=8 Hz, 1H), 7.19 (m, 1H), 7.27 (m, 4H) Mass SpectralAnalysis, m/z ESI 336 (M+H⁺).

Example 2A Preparation of 2.2

To a solution of 1.2 (72.69 g, 238 mmol) in N,N-dimethylformamide (500mL) was added imidazole (43.13 g, 309 mmol), N,N-dimethylaminopyridine(DMAP) (2.9 g, 23.8 mmol) and 2.1 (43.13 g, 286 mmol). The reactionmixture was stirred at room temperature for 16 hours. The reactionmixture was then poured into water and extracted with hexanes. Thecombined organic extracts were washed successively with water and brinesolution, dried over sodium sulfate and concentrated under reducedpressure. The crude product was purified by column chromatography(eluent: hexane/ethyl acetate mixtures of increasing polarity). Yield:86% ¹H NMR (400 MHz, CDCl₃) δ: 0.18 (s, 6H), 0.62 (d, J=6 Hz, 3H), 0.98(s, 9H), 1.26 (s, 1H), 1.34 (s, 3H), 1.46 (s, 9H), 1.96 (m, 1H), 2.17(m, 1H), 3.03 (m, 1H), 3.30 (m, 1H), 3.79 (m, 0.6H), 3.88 (m, 0.4H),4.06 (m, 0.5H), 4.23 (m, 0.5H), 6.67 (dd, J=8 Hz and 2 Hz, 1H), 6.73 (s,1H), 6.84 (d, J=7 Hz, 1H), 7.16 (t, J=8 Hz, 1H)

Mass Spectral Analysis, m/z ESI 420 (M+H⁺)

Preparation of 2.3

An oven dried flask under nitrogen atmosphere was charged with asolution of 2.2 (5.73 g, 13.64 mmol) andN,N,N′,N′-tetramethylethylenediamine (TMEDA) in diethyl ether (30 mL).The solution was cooled to −78° C. and sec-butyl lithium (1.4M incyclohexane, 14.6 mL, 20.46 mmol) was added drop wise over 30 minutes.After stirring at −78° C. for 4.5 hours, carbon dioxide was bubbledthrough the solution and the reaction mixture was allowed to warm toroom temperature overnight. The mixture was poured into saturatedammonium chloride solution and the aqueous layer extracted once withdiethyl ether. The ether extract was washed with water, brine, driedover sodium sulfate, filtered and concentrated under reduced pressure.The crude product purified by column chromatography (eluent:dichloromethane/methanol/acetic acid mixtures of increasing polarity).Yield: 73% ¹H NMR (400 MHz, CDCl₃) δ: 0.19 (s, 6H), 0.69 (d, J=7 Hz,3H), 0.98 (s, 9H), 1.37 (s, 3H), 1.46 (s, 9H), 2.01 (dd, J=14 Hz and 6Hz, 2H), 2.40 (t, J=12 Hz, 1H), 3.37 (dd, J=14 Hz and 8 Hz, 1H), 3.74(m, 1H), 4.30 (dd, J=11 Hz and 6 Hz, 1H), 6.67 (dd, J=8 Hz and 2 Hz,1H), 6.77 (s, 1H), 6.88 (d, J=7 Hz, 1H), 7.14 (t, J=8 Hz, 1H)

Mass Spectral Analysis, m/z ESI 464 (M+H⁺)

Preparation of 2.5

To a stirred solution of 2.3 (1 g, 2.16 mmol) in acetonitrile (10 mL)under a nitrogen atmosphere was added, sequentially,diisopropylethylamine (1.11 mL, 8.64 mmol), 2.4 (0.325 g, 2.59 mmol) andO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) (1.04 g, 3.24 mmol). The reaction was stirred at room temperatureovernight, poured into saturated ammonium chloride solution andextracted with ethyl acetate. The organic extracts were washed withbrine, dried over sodium sulfate, filtered and concentrated underreduced pressure. The crude product was purified by columnchromatography (eluent: hexane/ethyl acetate mixtures of increasingpolarity). Yield: 95% ¹H NMR (400 MHz, CDCl₃) δ: 0.18 (s, 6H), 0.53 (d,J=6 Hz 3H), 0.98 (s, 9H), 1.35 (s, 3H), 1.48 (s, 9H), 2.39 (t, J=13 Hz,1H), 3.04 (dd, J=14 Hz and 9 Hz, 1H), 3.76 (s, 3H), 3.89 (dd, J=14 Hzand 6 Hz, 1H), 4.05 (dd, J=10 Hz and 5 Hz, 2H), 4.35 (dd, J=11 Hz and 6Hz, 1H), 6.60 (br s, 1H), 6.67 (dd, J=8 Hz and 2 Hz, 1H), 6.76 (t, J=2Hz, 1H), 6.87 (dd, J=8 Hz and 1 Hz, 1H), 7.14 (t, J=8 Hz, 3H) MassSpectral Analysis, m/z ESI 535 (M+H⁺)

Preparation of 2.6

To a solution of 2.5 (1.55 g, 2.90 mmol) in methanol (20 mL) was added a4M anhydrous solution of hydrogen chloride in dioxane (2.2 mL, 8.8 mmol)and the mixture was heated to reflux for 2 hours. Triethylamine (3.51 g,34.8 mmol) was then added and the mixture was heated to reflux for 60hours. The reaction mixture was concentrated under reduced pressure. Thecrude product was purified by column chromatography (eluent:dichloromethane/methanol mixtures of increasing polarity). Yield: 100%¹H NMR (400 MHz, CDCl₃) δ: 0.64 (d, J=6 Hz, 3H), 1.43 (s, 3H), 1.59 (s,1H), 2.16 (m, 1H), 2.22 (t, J=13 Hz, 1H), 2.37 (m, 1H), 3.16 (dd, J=14Hz and 3 Hz, 1H), 3.49 (s, 1H), 4.23 (dd, J=14 Hz and 3 Hz, 1H), 4.50(dd, J=14 Hz and 3 Hz, 1H), 6.26 (br s, 1H), 6.70 (m, 2H), 6.81 (d, J=8Hz, 1H), 7.20 (t, J=8 Hz, 1H) Mass Spectral Analysis, m/z ESI 287(M−H⁺).

Preparation of 2.7

To a solution of 2.6 (0.98 g, 3.4 mmol) in anhydrous tetrahydrofuran(100 mL) was added borane-dimethyl sulfide complex (2M solution intetrahydrofuran, 5.8 mL, 13.6 mmol) and the reaction heated to refluxunder a nitrogen atmosphere for 16 hours. The mixture was then cooled to0° C. Methanol (20 mL) was added to the reaction mixture which wasstirred at 0° C. for 1 hour. A 2M anhydrous solution of hydrogenchloride in diethyl ether (20 mL) was then added to the reactionmixture, which was heated to reflux for 1 hour. After cooling, aqueousammonium hydroxide solution (5 mL) was added to the mixture, which wasstirred for 10 minutes at room temperature. The mixture was concentratedunder reduced pressure. The residue was dissolved in methanol (20 mL)and concentrated under reduced pressure. This process was repeated 3times. The crude product was purified by column chromatography (eluent:dichloromethane/methanol/ammonium hydroxide mixtures of increasingpolarity). Yield: 73% ¹H NMR (400 MHz, CDCl₃) δ: 0.79 (d, J=8 Hz, 3H),1.36 (s, 3H), 1.46 (d, J=12 Hz, 1H), 1.95 (t, J=12 Hz, 1H), 2.03 (br s,1H), 2.17 (dt, J=11 Hz and 7 Hz, 1H), 2.25 (t, J=11 Hz, 1H), 2.52 (dd,J=11 Hz and 2 Hz, 1H), 2.74 (m, 3H), 3.02 (m, 3H), 6.60 (s, 1H), 6.63(dd, J=9 Hz and 1 Hz, 1H), 6.78 (d, J=9 Hz, 1H), 7.19 (t, J=8 Hz, 1H)

Mass Spectral Analysis, m/z ESI 261(M+H⁺).

Preparation of 2A

A solution of 2.7 (0.1 g, 0.38 mmol) in tetrahydrofuran (5 mL) wastreated sequentially with triethylamine (0.115 g, 1.14 mmol) and 2.8(0.13 g, 0.84 mmol) and the mixture was stirred at room temperature for2 hours. A 1N aqueous solution of sodium hydroxide (5 mL) was added tothe mixture, which was stirred at room temperature for a further 12hours. The mixture was poured into saturated ammonium chloride solutionand extracted with ethyl acetate. The organic extracts were washed withwater, brine, dried over sodium sulfate, filtered and concentrated underreduced pressure. The crude product was purified by columnchromatography (eluent: dichloromethane/methanol mixtures of increasingpolarity). Yield: 96% ¹H NMR (400 MHz, CD₃OD), δ: 0.72 (d, J=7 Hz, 1H),0.75 (d, J=7 Hz, 2H), 1.13 (s, 1.5H), 1.30 (s, 1.5H), 1.55 (d, J=14 Hz,0.5H), 1.79 (m, 1H), 1.89 (d, J=11 Hz, 0.5H), 1.98 (m, 1.4H), 2.04 (m,1H), 2.19 (m, 0.6H), 2.53 (m, 2H), 2.65 (m, 1.7H), 2.86 (m, 1.3H), 3.78(d, J=15 Hz, 1.5H), 3.86 (d, J=15 Hz, 1H), 3.96 (dd, J=13 Hz and 2 Hz,0.5H), 4.43 (dt, J=13 Hz and 2 Hz, 0.5H), 4.49 (dd, J=13 Hz and 2 Hz,0.5H), 6.57 (d, J=8 Hz, 1H), 6.65 (s, 1H), 6.70 (s, 1H), 6.74 (d, J=8Hz, 1H), 7.09 (m, 1H), 7.25 (m, 1H), 7.32 (m, 3H) Mass SpectralAnalysis, m/z ESI 379 (M+H⁺)

Example 2B Preparation of 2B

To a solution of 2A (0.1 g, 0.26 mmol) in anhydrous tetrahydrofuran (10mL) was added borane-dimethyl sulfide complex (2M solution intetrahydrofuran, 0.4 mL, 0.8 mmol) and the reaction heated to refluxunder a nitrogen atmosphere for 16 hours. The mixture was then cooled to0° C. Methanol (5 mL) was added to the reaction mixture which wasstirred at 0° C. for 1 hour. A 2M anhydrous solution of hydrogenchloride in diethyl ether (2.5 mL) was then added to the reactionmixture, which was then heated to reflux for 1 hour. The mixture wascooled to room temperature. Aqueous ammonium hydroxide solution (2.5 mL)was added to the mixture, which was stirred for 10 minutes at roomtemperature. The mixture was concentrated under reduced pressure. Theresidue was dissolved in methanol and the solution was concentratedunder reduced pressure. This process was repeated 3 times. The crudeproduct was purified by column chromatography (eluent:dichloromethane/methanol/ammonium hydroxide mixtures of increasingpolarity). Yield: 42% ¹H NMR (400 MHz, CD₃OD) δ: 0.76 (d, J=7 Hz, 3H),1.36 (s, 3H), 1.53 (d, J=13 Hz, 1H), 1.65 (m, 0.5H), 1.93 (t, J=13 Hz,1H), 1.98 (m, 0.5H), 2.07 (m, 1H), 2.16 (t, J=11 Hz, 1H), 2.44 (m, 2H),2.61 (d, J=12 Hz, 1H), 2.71 (m, 2H), 2.79 (d, J=10 Hz, 1H), 2.87 (m,2H), 3.00 (d, J=9 Hz, 1H), 3.05 (d, J=9 Hz, 1H), 3.58 (m, 1H), 6.58 (dd,J=7 Hz and 2 Hz, 1H), 6.70 (s, 1H), 6.74 (d, J=8 Hz, 1H), 7.10 (t, J=8Hz, 1H), 7.19 (m, 1H), 7.24 (m, 2H), 7.28 (m, 2H) Mass SpectralAnalysis, m/z ESI 365 (M+H⁺)

Example 2C Preparation of 2C

A solution of 2.7 (0.1 g, 0.38 mmol) in tetrahydrofuran (5 mL) wastreated with triethylamine (0.115 g, 1.14 mmol) and 2.9 (0.12 g, 0.84mmol) and the mixture stirred at room temperature for 3 hours. A 1Naqueous solution of sodium hydroxide (5 mL) was added to the mixture,which was stirred at room temperature for a further 12 hours. Themixture was poured into saturated ammonium chloride solution andextracted with ethyl acetate. The organic extracts were washed withwater and brine, dried over sodium sulfate, filtered and concentratedunder reduced pressure. The crude product was purified by columnchromatography (eluent: dichloromethane/methanol/ammonium hydroxidemixtures of increasing polarity). Yield: 57% ¹H NMR (400 MHz, CD₃OD), δ:0.78 (br s, 3H), 1.29 (br s, 1.5H), 1.37 (br s, 1.5H), 1.63 (m, 0.5H),1.82 (m, 0.5H), 1.99 (m, 0.5H), 2.06 (br s, 1H), 2.25-2.35 (m, 1.4H),2.38 (m, 0.6H), 2.61 (m, 1H), 2.70 (m, 1H), 2.79 (dd, J=12 Hz and 2 Hz,1H), 2.86 (m, 0.5H), 3.06 (m, 1H), 3.37 (m, 1H), 3.59 (m, 1H), 4.60 (m,1H), 6.58 (m, 1H), 6.67 (m, 1H), 6.77 (m, 1H), 7.11 (m, 1H), 7.44 (m,2H), 7.48 (m, 3H) Mass Spectral Analysis, m/z ESI 365 (M+H⁺)

Example 2D Preparation of 2D

To a solution of 2C (0.07 g, 0.19 mmol) in anhydrous tetrahydrofuran (10mL) was added borane-dimethyl sulfide complex (2M solution intetrahydrofuran, 0.3 mL, 0.6 mmol) and the reaction heated to refluxunder a nitrogen atmosphere for 16 hours. The mixture was then cooled to0° C. Methanol (5 mL) was added to the reaction mixture which wasstirred at 0° C. for 1 hour. A 2M anhydrous solution of hydrogenchloride in diethyl ether (2.5 mL) was then added to the reactionmixture, which was then heated to reflux for 1 hour. The mixture wascooled to room temperature. Aqueous ammonium hydroxide solution (2.5 mL)was added to the mixture, which was stirred for 10 minutes at roomtemperature. The mixture was concentrated under reduced pressure. Theresidue was dissolved in methanol and the solution was concentratedunder reduced pressure. This process was repeated 3 times. The crudeproduct was purified by column chromatography (eluent:dichloromethane/methanol/ammonium hydroxide mixtures of increasingpolarity). Yield: 100% ¹H NMR (400 MHz, CD₃OD) δ: 0.73 (d, J=7 Hz, 3H),1.32 (s, 3H), 1.41 (d, J=13 Hz, 1H), 1.65 (m, 1H), 1.84 (m, 2H), 2.00(m, 1H), 2.33 (m, 1H), 2.43 (t, J=11 Hz, 1H), 2.56 (dd, J=11 Hz and 2Hz, 1H), 2.70 (m, 1H), 2.74 (m, 1H), 2.82 (dd, J=8 Hz and 2 Hz, 1H),3.56 (m, 2H), 3.58 (m, 1H), 6.56 (dd, J=8 Hz and 2 Hz, 1H), 6.68 (m,1H), 6.72 (d, J=8 Hz, 1H), 7.08 (t, J=8 Hz, 1H), 7.27 (m, 1H), 7.34 (m,4H)

Mass Spectral Analysis, m/z ESI 351 (M+H⁺)

Example 2E Preparation of 2.10

To a stirred solution of 2.7 (1 g, 3.85 mmol) in tetrahydrofuran (20 mL)under nitrogen at 0° C., was added triethylamine (2.14 mL, 15.40 mmol)and 1.2 (1.84 g, 8.46 mmol). The solution was stirred at roomtemperature for 18 hours. The mixture was concentrated under reducedpressure and the residue was dissolved in ethyl acetate (20 mL). Thesolution was then washed with 0.5M aqueous solution of hydrochloric acid(2×25 mL) and dried over sodium sulfate. The mixture was filtered andthe residue concentrated under reduced pressure. The crude product waspurified by column chromatography (eluent: hexane/ethyl acetate mixturesof increasing polarity). Yield: 74% ¹H NMR (400 MHz, CDCl₃) δ: 0.73 (d,J=7 Hz, 3H), 1.35 (s, 3H), 1.48 (s, 9H), 1.52 (s, 1H), 1.66 (s, 1H),1.97 (m, 2H), 2.19 (dt, J=12 Hz and 4 Hz, 1H), 2.26 (m, 1H), 2.56 (dd,J=12 Hz and 2 Hz, 1H), 2.68 (m, 3H), 3.02 (br s, 1H), 4.00 (br s, 1H),6.64 (dd, J=8 Hz and 2 Hz, 1H), 6.74 (t, J=2 Hz, 1H), 6.80 (d, J=8 Hz1H), 7.17 (t, J=8 Hz 1H) Mass Spectral Analysis, m/z ESI 361 (M+H⁺)

Preparation of 2.11

To a stirred solution of 2.10 (1.03 g, 2.86 mmol) inN,N-dimethylformamide (10 mL) was added 1.4 (0.41 mL, 3.43 mmol) andpotassium carbonate (1.18 g, 8.58 mmol) and the reaction mixture wasstirred at room temperature for 18 hours. The reaction mixture was thenpoured into water (20 mL) and extracted with hexanes. The combinedorganics were washed with water, brine and dried over sodium sulfate.The mixture was filtered and the filtrate was concentrated under reducedpressure. The desired product used for next step without furtherpurification.

Yield: 99% ¹H NMR (400 MHz, CDCl₃) δ: 0.75 (d, J=7 Hz, 3H), 1.33 (s,3H), 1.48 (s, 10H), 1.51 (s, 1H), 1.60 (s, 1H), 1.87 (t, J=12 Hz, 1H),2.01 (m, 1H), 2.18 (m, 1H), 2.52 (dd, J=11 Hz and 2 Hz, 2H), 2.67 (m,2H), 2.96 (br s, 1H), 3.98 (br s, 1H), 5.05 (s, 2H), 6.81 (dd, J=8 Hzand

-   -   2 Hz, 1H), 6.89 (m, 2H), 7.23 (d, J=9 Hz 1H), 7.34 (m, 1H), 7.39        (t, J=8 Hz, 2H), 7.45 (d, J=    -   9 Hz, 2H) Mass Spectral Analysis, m/z ESI 451 (M+H⁺)

Preparation of 2.12

To a stirred solution of 2.11 (1.27 g, 2.82 mmol) in methanol (10 mL)was added a 2M anhydrous solution of hydrogen chloride in diethyl ether(6 mL) and the reaction mixture was stirred at room temperature for 18hours. The mixture was concentrated under reduced pressure. A saturatedsodium bicarbonate solution (20 mL) and ethyl acetate (20 mL) were addedto the residue and the resultant mixture was stirred at room temperaturefor 1 hour. The layers were separated and the organic layer was washedwith brine and dried over sodium sulfate. The mixture was filtered andthe filtrate was concentrated under reduced pressure. The desiredproduct was used for the next step without further purification. Yield:100% ¹H NMR (400 MHz, CDCl₃) δ: 0.75 (d, J=7 Hz, 3H), 1.34 (s, 3H), 1.45(d, J=13 Hz, 1H), 1.88 (t, J=12 Hz, 1H), 2.00 (m, 1H), 2.27 (m, 2H),2.48 (dd, J=12 Hz and 2 Hz, 1H), 2.60 (t, J=11 Hz, 1H), 2.70 (m, 2H),2.94 (m, 2H), 2.99 (m, 2H), 5.05 (s, 2H), 6.79 (dd, J=9 Hz and 2 Hz,1H), 6.87 (m, 2H), 7.23 (t, J=8 Hz 1H), 7.32 (m, 1H), 7.38 (t, J=8 Hz,2H), 7.44 (m, 2H)

Mass Spectral Analysis, m/z ESI 351 (M+H⁺)

Preparation of 2.14

To a solution of 2.12 (0.5 g, 1.43 mmol) in tetrahydrofuran (10 mL) wasadded with triethylamine (0.6 mL, 4.26 mmol) and 2.13 (0.22 mL, 1.72mmol). The mixture was stirred at room temperature for 2 hours. Themixture was poured into saturated ammonium chloride solution andextracted with ethyl acetate. The organic extracts were washed withwater and brine, dried over sodium sulfate, filtered and concentratedunder reduced pressure. The crude product was purified by columnchromatography (eluent: hexane/ethyl acetate mixtures of increasingpolarity). Yield: 70% ¹H NMR (400 MHz, CDCl₃), δ: 0.64 (d, J=7 Hz, 3H),1.33 (s, 3H), 1.49 (dd, J=12 Hz and 2 Hz, 1H), 1.78 (t, J=12 Hz, 1H),1.99 (m, 1H), 2.09 (t, J=11 Hz, 1H), 2.39 (m, 1H), 2.48 (m, 3H), 2.71(m, 2H), 3.60 (dt, J=11 Hz and 2 Hz, 1H), 3.69 (dt, J=8 Hz and 2 Hz,1H), 5.04 (s, 2H), 6.78 (m, 1H), 6.82 (m, 2H), 7.22 (t, J=8 Hz, 1H),7.34 (m, 1H), 7.39 (t, J=8 Hz, 2H), 7.45 (d, J=8 Hz, 2H), 7.56 (m, 2H),7.61 (m, 1H), 7.78 (d, J=8 Hz, 1H) Mass Spectral Analysis, m/z ESI 491(M+H⁺)

Preparation of 2E

To a solution of 2.14 (0.52 g, 1.06 mmol) in ethanol (20 mL) was added10% palladium on charcoal (0.05 g) and the mixture stirred at roomtemperature under a hydrogen atmosphere for 16 hours. The mixture wasthen filtered through celite. The celite was washed with ethanol and thefiltrate was concentrated under reduced pressure. The crude product waspurified by column chromatography (eluent:dichloromethane/methanol/ammonium hydroxide mixtures of increasingpolarity). Yield: 85% ¹H NMR (400 MHz, CD₃OD) δ: 0.65 (d, J=7 Hz, 3H),1.31 (s, 3H), 1.52 (d, J=12 Hz, 1H), 1.77 (t, J=12 Hz, 1H), 2.00 (m,1H), 2.10 (t, J=11 Hz, 1H), 2.30 (dt, J=11 Hz and 3 Hz, 1H), 2.37 (m,1H), 2.43 (dd, J=12 Hz and 3 Hz, 1H), 2.52 (m, 2H), 3.60 (d, J=11 Hz,1H), 3.65 (d, J=11 Hz, 1H), 6.57 (dd, J=8 Hz and 3 Hz, 1H), 6.67 (s,1H), 6.70 (d, J=7 Hz, 1H), 7.08 (t, J=8 Hz, 1H), 7.63 (m, 2H), 7.68 (m,1H), 7.79 (d, J=8 Hz, 2H) Mass Spectral Analysis, m/z ESI 401 (M+H⁺).

Example 2F Preparation of 2.16

To a solution of 2.12 (0.5 g, 1.43 mmol) in dichloromethane (10 mL) wasadded 2.15 (0.5 g, 2.71 mmol), triethylamine (0.4 mL, 2.86 mmol) andcupric acetate (0.2 g, 1.43 mmol). The mixture was stirred at roomtemperature for 2 days. The mixture was poured into water and extractedwith dichloromethane. The organic extracts were washed with water andbrine, dried over sodium sulfate, filtered and concentrated underreduced pressure. The crude product was purified by columnchromatography (eluent: dichloromethane/methanol/ammonium hydroxidemixtures of increasing polarity). Yield: 30% ¹H NMR (400 MHz, CDCl₃), δ:0.78 (d, J=7 Hz, 3H), 1.37 (s, 3H), 1.55 (t, J=12 Hz, 1H), 2.02 (m, 2H),2.44 (m, 1H), 2.49 (m, 1H), 2.60 (t, J=12 Hz, 1H), 2.75 (dd, J=11 Hz and3 Hz, 1H), 2.81 (dd, J=11 Hz and 3 Hz, 1H), 2.94 (dt, J=12 Hz and 3 Hz,1H), 3.51 (dd, J=11 Hz and 2 Hz, 1H), 3.57 (d, J=11 Hz, 1H), 5.06 (s,2H), 6.81 (dd, J=8 Hz and 2 Hz, 1H), 6.85 (d, J=8 Hz, 1H), 6.88 (d, J=5Hz, 1H), 6.91 (s, 2H), 6.96 (d, J=7 Hz, 2H), 7.28 (m, 2H), 7.33 (d, J=7Hz, 1H), 7.39 (t, J=8 Hz, 2H), 7.46 (d, J=7 Hz, 2H) Mass SpectralAnalysis, m/z ESI 427 (M+H⁺)

Preparation of 2F

To a solution of 2.16 (0.18 g, 0.42 mmol) in ethanol (20 mL) was added10% palladium on charcoal (0.02 g) and the mixture stirred at roomtemperature under a hydrogen atmosphere for 16 hours. The mixture wasthen filtered through celite. The celite was washed with ethanol and thefiltrate evaporated under reduced pressure. The crude product waspurified by column chromatography (eluent:dichloromethane/methanol/ammonium hydroxide mixtures of increasingpolarity). Yield: 50% ¹H NMR (400 MHz, CD₃OD) δ: 0.79 (d, J=7 Hz, 3H),1.37 (s, 3H), 1.61 (d, J=12 Hz, 1H), 1.99 (t, J=12 Hz, 1H), 2.08 (m,1H), 2.44 (dt, J=11 Hz and 2 Hz, 1H), 2.54 (m, 2H), 2.63 (dd, J=11 Hzand 2 Hz, 1H), 2.77 (dd, J=12 Hz and 3 Hz, 1H), 2.84 (m, 1H), 2.90 (m,1H), 3.55 (t, J=11 Hz, 2H), 6.58 (dd, J=8 Hz and 2 Hz, 1H), 6.74 (m,1H), 6.77 (d, J=8 Hz, 1H), 6.83 (t, J=7 Hz, 1H), 6.99 (d, J=8 Hz, 2H),7.11 (t, J=8 Hz, 1H), 7.23 (t, J=8 Hz, 2H) Mass Spectral Analysis, m/zESI 337 (M+H⁺).

Example 3A Preparation of 3.2

To a stirred solution of 2.3 (2 g, 4.32 mmol) in acetonitrile (20 mL)under a nitrogen atmosphere was added, sequentially,diisopropylethylamine (3 mL, 17.28 mmol), 3.1 (1.04 g, 5.18 mmol) andO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) (2.08 g, 6.48 mmol). The reaction was stirred at room temperatureovernight, poured into saturated ammonium chloride solution andextracted with ethyl acetate. The organic extracts were washed withsaturated brine, dried over sodium sulfate, filtered and concentratedunder reduced pressure. The crude product was purified by columnchromatography (eluent: hexane/ethyl acetate mixtures of increasingpolarity). Yield: 82% ¹H NMR (400 MHz, CDCl₃) δ: 0.18 (s, 6H), 0.54 (d,J=6 Hz, 3H), 0.98 (s, 9H), 1.34 (s, 3H), 1.38 (s, 9H), 2.03 (m, 2H),2.40 (t, J=13 Hz, 1H), 3.03 (dd, J=13 Hz and 8 Hz, 1H), 3.74 (s, 3H),3.92 (dd, J=11 Hz and 8 Hz, 1H), 4.33 (dd, J=12 Hz and 6 Hz, 1H), 5.59(d, J=7 Hz, 1H), 6.68 (dd, J=8 Hz and 2 Hz, 1H), 6.75 (t, J=2 Hz, 1H),6.87 (d, J=8 Hz, 1H), 7.14 (t, J=8 Hz, 2H), 7.33 (m, 1H), 7.35 (m, 4H)Mass Spectral Analysis, m/z ESI 611 (M+H⁺)

Preparation of 3.3

To a solution of 3.2 (2.16 g, 3.54 mmol) in methanol (75 mL) was added a4M solution of anhydrous hydrogen chloride in dioxane (3.8 mL, 14.4mmol). The mixture was heated to reflux for 2 hours. The mixture wasconcentrated under reduced pressure and the residue taken up in ethylacetate (75 mL). A saturated solution of sodium bicarbonate was added tothe mixture which was stirred for 2 hours at room temperature. Thelayers were separated and the organic layer was washed with water,brine, dried over sodium sulfate, filtered and concentrated underreduced pressure. The crude product was washed with hexanes and used forthe next step without further purification. Yield: 95% ¹H NMR (400 MHz,CDCl₃) δ: 0.73 (d, J=7 Hz, 3H), 1.28 (s, 4H), 1.92 (m, 1H), 2.03 (m,1H), 2.81 (dd, J=12 Hz and 2 Hz, 1H), 3.29 (dd, J=12 Hz and 3 Hz, 1H),3.61 (dd, J=11 Hz and 4 Hz, 1H), 3.74 (s, 3H), 5.63 (d, J=13 Hz, 1H),6.64 (dd, J=8 Hz and 2 Hz, 1H), 6.72 (s, 1H), 6.79 (d, J=7 Hz, 1H), 7.15(t, J=8 Hz, 1H), 7.38 (m, 5H), 7.92 (d, J=7 Hz, 1H) Mass SpectralAnalysis, m/z ESI 397 (M+H⁺)

Preparation of 3.4

A solution of 3.3 (1.33 g, 3.36 mmol) in toluene (200 mL) was heated toreflux for 60 hours. The mixture was concentrated under reducedpressure. The crude product was purified by column chromatography(eluent: dichloromethane/methanol mixtures of increasing polarity).Yield: 47% ¹H NMR (400 MHz, CDCl₃) δ: 0.64 (d, J=7 Hz, 3H), 1.39 (s,3H), 2.11 (m, 1H), 2.26 (t, J=13 Hz, 1H), 2.43 (dd, J=14 Hz and 2 Hz,1H), 3.12 (dd, J=14 Hz and 3 Hz, 1H), 4.35 (dd, J=12 Hz and 3 Hz, 1H),4.41 (dd, J=14 Hz and 2 Hz, 1H), 5.16 (s, 1H), 6.51 (s, 1H), 6.67 (dd,J=8 Hz and 2 Hz, 1H), 6.73 (s, 1H), 6.79 (d, J=8 Hz, 2H), 7.19 (t, J=8Hz, 1H), 7.39 (m, 5H) Mass Spectral Analysis, m/z ESI 363 (M−H⁺)

Preparation of 3A

To a solution of 3.4 (0.57 g, 1.57 mmol) in anhydrous tetrahydrofuran(10 mL) was added borane-dimethyl sulfide complex (2M solution intetrahydrofuran, 4.7 mL, 9.4 mmol) and the reaction was heated to refluxunder a nitrogen atmosphere for 16 hours. The mixture was then cooled to0° C. Methanol (20 mL) was added to the reaction mixture, which wasstirred at 0° C. for 1 hour. A 2M anhydrous solution of hydrogenchloride in diethyl ether (5 mL) was then added to the reaction, whichwas heated to reflux for 1 hour. After cooling to room temperature, anaqueous ammonium hydroxide solution (5 mL) was added to the mixture,which was stirred for 10 minutes at room temperature. The mixture wasconcentrated under reduced pressure. The residue was dissolved inmethanol and concentrated under reduced pressure. This process wasrepeated 3 times. The crude product was purified by columnchromatography (eluent: dichloromethane/methanol/ammonium hydroxidemixtures of increasing polarity).

Yield: 69% ¹H NMR (400 MHz, CD₃OD) δ: 0.79 (d, J=7 Hz, 3H), 1.38 (s,3H), 1.57 (d, J=13 Hz, 1H), 1.95 (t, J=12 Hz, 1H), 2.06 (m, 1H), 2.30(t, J=13 Hz, 1H), 2.49 (t, J=11 Hz, 1H), 2.57 (dd, J=12 Hz and 2 Hz,1H), 2.81 (m, 3H), 3.06 (dd, J=13 Hz and 2 Hz, 1H), 4.04 (dd, J=11 Hzand 3 Hz, 1H), 6.59 (dd, J=8 Hz and 2 Hz, 1H), 6.72 (t, J=2 Hz, 1H),6.76 (d, J=7 Hz, 1H), 7.11 (t, J=8 Hz, 1H), 7.30 (m, 1H), 7.36 (t, J=7Hz, 2H), 7.41 (d, J=7 Hz, 2H) Mass Spectral Analysis, m/z ESI 337 (M+H⁺)

Example 3B Preparation of 3B

To a solution of 3A (0.1 g, 0.30 mmol) in tetrahydrofuran (5 mL) andethanol (5 mL) was added triethylamine (0.067 g, 0.66 mmol) and 3.5(0.05 mL, 0.60 mmol). After 10 minutes sodium cyanoborohydride (0.03 g,0.36 mmol) was added to the mixture, which was stirred at roomtemperature for 60 hours. The mixture was concentrated under reducedpressure. The crude product was purified by column chromatography(eluent: dichloromethane/methanol/ammonium hydroxide mixtures ofincreasing polarity).

Yield: 76% ¹H NMR (400 MHz, CD₃OD) δ: 0.77 (d, J=7 Hz, 3H), 1.37 (s,3H), 1.57 (d, J=13 Hz, 1H), 1.96 (t, J=13 Hz, 1H), 2.07 (s, 4H), 2.24(t, J=11 Hz, 1H), 2.32 (t, J=11 Hz, 1H), 2.55 (m, 1H), 2.66 (m, 2H),2.74 (m, 1H), 2.92 (d, J=10 Hz, 1H), 3.24 (d, J=9 Hz, 1H), 6.58 (dd, J=8Hz and 2 Hz, 1H), 6.72 (t, J=2 Hz, 1H), 6.76 (d, J=8 Hz, 1H), 7.11 (t,J=8 Hz, 1H), 7.29 (m, 1H), 7.36 (m, 4H) Mass Spectral Analysis, m/z ESI351 (M+H⁺)

Example 3C Preparation of 3.7

To a solution of 3A (0.2 g, 0.60 mmol) in N,N-dimethylformamide (10 mL)was added 3.6 (0.13 mL, 0.89 mmol) and potassium carbonate (0.25 g, 1.80mmol). The reaction was stirred at room temperature for 3 hours, pouredinto a saturated solution of ammonium chloride and extracted with ethylacetate. The organic extracts were washed with saturated brine, driedover sodium sulfate, filtered and concentrated under reduced pressure.The crude product was purified by column chromatography (eluent:hexane/ethyl acetate mixtures of increasing polarity). Yield: 49% ¹H NMR(400 MHz, CDCl₃), δ: 0.77 (d, J=7 Hz, 3H), 1.26 (br s, 2H), 1.37 (s,3H), 1.42 (s, 9H), 2.00 (t, J=12 Hz, 1H), 2.31 (t, J=11 Hz, 1H), 2.47(m, 1H), 2.62 (m, 1H), 2.70 (m, 2H), 2.79 (d, J=16 Hz, 1H), 3.06 (dd,J=11 Hz and 3 Hz, 1H), 3.18 (d, J=16 Hz, 1H), 3.71 (dd, J=11 Hz and 3Hz, 1H), 4.98 (m, 1H), 6.64 (dd, J=8 Hz and 2 Hz, 1H), 6.76 (s, 1H),6.84 (d, J=8 Hz, 1H), 7.18 (t, J=8 Hz, 1H), 7.26 (m, 1H), 7.33 (m, 2H),7.41 (d, J=7 Hz, 1H) Mass Spectral Analysis, m/z ESI 451 (M+H⁺)

Preparation of 3C

A solution of 3.7 (0.13 g, 0.29 mmol) in dioxane (5 mL) and water (5 mL)was treated with a 1M anhydrous solution of hydrogen chloride in diethylether (1 mL, 1 mmol). The reaction mixture was stirred at roomtemperature for 2 days and concentrated under reduced pressure. Theresidue was triturated with acetonitrile. The precipitate was collectedby filtration and further washed with acetonitrile (3 mL). Yield: 67% ¹HNMR (400 MHz, CD₃OD), δ: 0.90 (d, J=7 Hz, 3H), 1.56 (s, 3H), 2.06 (d,J=14 Hz, 1H), 2.35 (t, J=14 Hz, 1H), 2.45 (dd, J=14 Hz and 2 Hz, 1H),3.41 (dd, J=13 Hz and 2 Hz, 1H), 3.59 (d, J=13 Hz, 1H), 3.71 (dd, J=13Hz and 4 Hz, 1H), 3.80 (m, 4H), 3.94 (t, J=12 Hz, 1H), 4.25 (m, 1H),5.14 (dd, J=12 Hz and 3 Hz, 1H), 6.67 (dd, J=8 Hz and 2 Hz, 1H), 6.74(s, 1H), 6.79 (d, J=8 Hz, 1H), 7.17 (t, J=8 Hz, 1H), 7.51 (m, 3H), 7.63(m, 2H) Mass Spectral Analysis, m/z ESI 395 (M+H⁺)

Example 3D Preparation of 3.9

To a solution of 3A (0.2 g, 0.60 mmol) in methanol (10 mL) was added 3.8(0.13 mL, 0.89 mmol) and triethylamine (0.25 mL, 1.80 mmol). Thereaction was heated to reflux for 18 hours and then concentrated underreduced pressure. The crude product was purified by columnchromatography (eluent: hexane/ethyl acetate mixtures of increasingpolarity). Yield: 62%

¹H NMR (400 MHz, CDCl₃), δ: 0.71 (d, J=7 Hz, 3H), 1.37 (s, 3H), 1.42 (s,9H), 1.53 (d, J=13 Hz, 1H), 1.97 (m, 1H), 2.11 (t, J=12 Hz, 1H), 2.30(m, 5H), 2.54 (t, J=13 Hz, 2H), 2.66 (dd, J=11 Hz and 3 Hz, 1H), 2.74(dd, J=12 Hz and 3 Hz, 1H), 2.85 (m, 1H), 3.07 (dd, J=11 Hz and 2 Hz,1H), 3.48 (dd, J=11 Hz and 3 Hz, 1H), 6.66 (dd, J=8 Hz and 2 Hz, 1H),6.80 (d, J=2 Hz, 2H), 7.17 (t, J=8 Hz, 1H), 7.31 (m, 5H) Mass SpectralAnalysis, m/z ESI 465 (M+H⁺)

Preparation of 3D

A solution of 3.9 (0.17 g, 0.37 mmol) in dioxane (5 mL) and water (5 mL)was treated with a 1M anhydrous solution of hydrogen chloride in diethylether (1 mL, 1 mmol). The reaction mixture was stirred at roomtemperature for 2 days and concentrated under reduced pressure. Theresidue was triturated with dichloromethane. The precipitate wascollected by filtration and further washed with dichloromethane (3 mL).Yield: 88% ¹H NMR (400 MHz, CD₃OD), δ: 0.94 (d, J=7 Hz, 3H), 1.56 (s,3H), 2.11 (d, J=13 Hz, 1H), 2.43 (m, 2H), 2.78 (m, 2H), 3.22 (m, 1H),3.35 (m, 1H), 3.45 (m, 1H), 3.81 (m, 3H), 4.06 (m, 2H), 4.42 (t, J=12Hz, 1H), 5.18 (d, J=11 Hz, 1H), 6.67 (dd, J=8 Hz and 2 Hz, 1H), 6.74 (s,1H), 6.79 (d, J=8 Hz, 1H), 7.18 (t, J=8 Hz, 1H), 7.56 (m, 3H), 7.63 (brs, 2H)

Mass Spectral Analysis, m/z ESI 409 (M+H⁺)

Example 3E Preparation of 3E

To a solution of 3A (1 g, 2.98 mmol) in ethanol (20 mL) was added 3.10(0.95 g, 8.93 mmol) and the reaction mixture was stirred at roomtemperature for 10 minutes. To this was then added borane-pyridinecomplex (BAP) (0.82 g, 8.93 mmol) and the reaction stirred at roomtemperature for 18 hours. The mixture was concentrated under reducedpressure. The residue was taken up in ethyl acetate. The mixture waswashed with a saturated aqueous sodium bicarbonate solution, water,brine, dried over magnesium sulfate, filtered and concentrated underreduced pressure. The crude product was purified by columnchromatography (eluent: dichloromethane/methanol/ammonium hydroxidemixtures of increasing polarity).

Yield: 71% ¹H NMR (400 MHz, CD₃OD) δ: 0.76 (d, J=7 Hz, 3H), 1.31 (s,3H), 1.38 (d, J=13 Hz, 1H), 1.89 (t, J=13 Hz, 1H), 2.04 (m, 2H), 2.32(t, J=11 Hz, 1H), 2.48 (m, 1H), 2.54 (dd, J=11 Hz and 2 Hz, 1H), 2.69(t, J=3 Hz, 1H), 2.72 (t, J=3 Hz, 1H), 2.79 (dd, J=11 Hz and 2 Hz, 1H),2.90 (d, J=13 Hz, 1H), 3.51 (dd, J=10 Hz and 3 Hz, 1H), 3.74 (d, J=13Hz, 1H), 6.55 (dd, J=7 Hz and 1 Hz, 1H), 6.67 (t, J=2 Hz, 1H), 6.71 (d,J=7 Hz, 1H), 7.08 (t, J=8 Hz, 1H), 7.21 (m, 1H), 7.28 (m, 5H), 7.37 (t,J=8 Hz, 2H), 7.53 (d, J=6 Hz, 2H),

Mass Spectral Analysis, m/z ESI 427 (M+H⁺)

Example 3F Preparation of 3.12

To a solution of 3E (0.9 g, 2.11 mmol) in dichloromethane (10 mL) at 0°C. under a nitrogen atmosphere was added 3.11 (0.83 g, 2.32 mmol) andtriethylamine (0.71 mL, 5.06 mmol). The reaction mixture was allowed towarm to room temperature overnight and the concentrated under reducedpressure. The residue was taken up in ethyl acetate. The organic mixturewas washed successively with brine, a 1N aqueous solution of sodiumhydroxide, brine, dried over sodium sulfate, filtered and concentratedunder reduced pressure. The crude product was purified by columnchromatography (eluent: hexane/ethyl acetate mixtures of increasingpolarity). Yield: 72% ¹H NMR (400 MHz, CDCl₃) δ: 0.75 (d, J=7 Hz, 3H),1.33 (s, 3H), 1.44 (d, J=12 Hz, 1H), 1.57 (s, 1H), 1.88 (t, J=12 Hz,1H), 2.05 (m, 1H), 2.32 (t, J=11 Hz, 1H), 2.44 (m, 1H), 2.51 (dd, J=12Hz and 2 Hz, 1H), 2.67 (dd, J=12 Hz and 3 Hz, 1H), 2.76 (dd, J=11 Hz and3 Hz, 1H), 2.83 (dd, J=11 Hz and 2 Hz, 1H), 2.88 (d, J=14 Hz, 1H), 3.51(dd, J=11 Hz and 3 Hz, 1H), 3.82 (d, J=13 Hz, 1H), 7.09 (m, 2H), 7.24(m, 4H), 7.30 (m, 4H), 7.37 (m, 3H), 7.53 (m, 1H) Mass SpectralAnalysis, m/z ESI 559 (M+H⁺)

Preparation of 3.13

To a solution of 3.12 (0.5 g, 0.90 mmol) in methanol (6 mL) anddimethylsulfoxide (8 mL) was added triethylamine (0.28 mL, 1.97 mmol).Carbon monoxide was then bubbled through the solution for 5 minutes.Palladium (II) acetate (0.02 g, 0.09 mmol) and1,1′-bis(diphenylphosphino)ferrocene (dppf) (0.1 g, 0.18 mmol) wereadded to the mixture. Carbon monoxide was bubbled through the reactionmixture for 15 minutes while the reaction was heated to 65° C. Thereaction mixture was heated at 65° C. under an atmosphere of carbonmonoxide for 18 hours. The reaction mixture was poured into water andextracted with ethyl acetate. The organic extracts were washed withwater, saturated brine solution, dried over sodium sulfate, filtered andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography (eluent: hexane/ethyl acetate mixtures ofincreasing polarity). Yield: 76% ¹H NMR (400 MHz, CD₃OD) δ: 0.72 (d, J=7Hz, 3H), 1.36 (s, 3H), 1.50 (d, J=13 Hz, 1H), 1.98 (t, J=13 Hz, 1H),2.11 (m, 2H), 2.35 (t, J=11 Hz, 1H), 2.54 (m, 2H), 2.74 (m, 2H), 2.84(dd, J=11 Hz and 2 Hz, 1H), 2.92 (d, J=13 Hz, 1H), 3.52 (dd, J=10 Hz and3 Hz, 1H), 3.74 (d, J=13 Hz, 1H), 3.89 (s, 3H), 7.22 (m, 1H), 7.28 (m,5H), 7.39 (m, 3H), 7.53 (d, J=8 Hz, 3H), 7.82 (dd, J=8 Hz and 2 Hz, 1H),7.90 (s, 1H)

Mass Spectral Analysis, m/z ESI 469 (M+H⁺)

Preparation of 3.14

A solution of 3.13 (0.29 g, 0.62 mmol) in tetrahydrofuran (4 mL) andwater (2 mL) was treated with lithium hydroxide monohydrate (0.08 g,1.86 mmol) and methanol (10 mL) and the mixture was stirred at roomtemperature for 2 days. The reaction mixture was neutralized to pH ˜6-7by addition of 1N aqueous solution of hydrochloric acid. The mixture wasthen concentrated under reduced pressure. The residue was taken up indichloromethane. The organic solution was dried over sodium sulfate,filtered and concentrated under reduced pressure. The product wasisolated without further purification. Yield: 100% ¹H NMR (400 MHz,CD₃OD) δ: 0.76 (d, J=7 Hz, 3H), 1.42 (s, 3H), 1.69 (d, J=13 Hz, 1H),2.14 (t, J=13 Hz, 1H), 2.27 (m, 1H), 2.34 (m, 1H), 2.80 (t, J=11 Hz,1H), 2.88 (dd, J=13 Hz and 2 Hz, 1H), 2.95 (dd, J=12 Hz and 2 Hz, 1H),3.02 (m, 3H), 3.11 (dd, J=12 Hz and 3 Hz, 1H), 3.75 (m, 2H), 7.22 (m,1H), 7.28 (m, 4H), 7.36 (m, 2H), 7.42 (m, 3H), 7.56 (d, J=7 Hz, 2H),7.81 (d, J=8 Hz, 1H), 7.90 (s, 1H) Mass Spectral Analysis, m/z ESI 455(M+H⁺)

Preparation of 3F

To a stirred solution of 3.14 (0.22 g, 0.48 mmol) inN,N-dimethylformamide (10 mL) were added, sequentially, triethylamine(0.15 mL, 1.06 mmol), ammonium chloride (0.1 g, 2.40 mmol) andO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) (0.23 g, 0.72 mmol). The reaction was stirred at room temperaturefor 4 hours, poured into saturated ammonium chloride solution andextracted with ethyl acetate. The organic extracts were washed withsaturated brine, dried over sodium sulfate and concentrated underreduced pressure. The crude product was purified by columnchromatography (eluent: dichloromethane/methanol/ammonium hydroxidemixtures of increasing polarity).

Yield: 91% ¹H NMR (400 MHz, CD₃OD) δ: 0.74 (d, J=7 Hz, 3H), 1.39 (s,3H), 1.64 (d, J=13 Hz, 1H), 2.06 (t, J=13 Hz, 1H), 2.22 (m, 2H), 2.59(t, J=12 Hz, 1H), 2.76 (m, 2H), 2.89 (m, 1H), 2.95 (m, 3H), 3.61 (dd,J=11 Hz and 3 Hz, 1H), 3.75 (d, J=13 Hz, 1H), 7.22 (m, 1H), 7.28 (m,6H), 7.40 (t, J=8 Hz, 3H), 7.47 (d, J=8 Hz, 1H), 7.54 (m, 2H), 7.68 (m,2H), 7.778 (s, 1H) Mass Spectral Analysis, m/z ESI 454 (M+H⁺)

Example 3G Preparation of 3G

To a solution of 3F (0.1 g, 0.22 mmol) in ethanol (20 mL) was added 10%palladium on charcoal (0.01 g) and the mixture stirred at roomtemperature under a hydrogen atmosphere for 16 hours. The mixture wasthen filtered through celite. The celite was washed with ethanol and thefiltrate was evaporated under reduced pressure. The crude product waspurified by column chromatography (eluent:dichloromethane/methanol/ammonium hydroxide mixtures of increasingpolarity). Yield: 12%

¹H NMR (400 MHz, CD₃OD) δ: 0.77 (d, J=7 Hz, 3H), 1.43 (s, 3H), 1.67 (d,J=12 Hz, 1H), 2.02 (t, J=12 Hz, 1H), 2.18 (m, 1H), 2.24 (t, J=11 Hz,1H), 2.46 (m, 1H), 2.58 (dd, J=11 Hz and 2 Hz, 1H), 2.79 (m, 3H), 3.04(dd, J=12 Hz and 3 Hz, 1H), 3.97 (dd, J=11 Hz and 3 Hz, 1H), 7.27 (m,1H), 7.33 (t, J=8 Hz, 2H), 7.42 (m, 3H), 7.52 (d, J=8 Hz, 1H), 7.70 (dd,J=8 Hz and 2 Hz, 1H), 7.83 (s, 1H) Mass Spectral Analysis, m/z ESI 364(M+H⁺).

Example 4 Preparation of 4.2

To a stirred solution of 2.3 (2 g, 4.32 mmol) in acetonitrile (20 mL)under a nitrogen atmosphere were added, sequentially,diisopropylethylamine (3 mL, 17.28 mmol), 4.1 (1.12 g, 5.18 mmol) andO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) (2.08 g, 6.48 mmol). The reaction mixture was stirred at roomtemperature overnight, poured into a saturated aqueous solution ofammonium chloride and extracted with ethyl acetate. The organic extractswere washed with saturated brine, dried over sodium sulfate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography (eluent: hexane/ethyl acetate mixtures ofincreasing polarity). Yield: 81% ¹H NMR (400 MHz, CDCl₃) δ: 0.18 (s,6H), 0.45 (d, J=7 Hz, 3H), 0.98 (s, 9H), 1.32 (s, 3H), 1.45 (s, 9H),1.98 (m, 2H), 2.33 (t, J=13 Hz, 1H), 2.89 (dd, J=14 Hz and 9 Hz, 1H),3.12 (t, J=6 Hz, 2H), 3.70 (s, 3H), 3.88 (dd, J=8 Hz and 3 Hz, 1H), 4.33(dd, J=12 Hz and 6 Hz, 1H), 4.84 (q, J=6 Hz, 1H), 6.66 (dd, J=8 Hz and 2Hz, 1H), 6.73 (t, J=2 Hz, 1H), 6.84 (d, J=8 Hz, 1H), 7.13 (m, 3H), 7.24(m, 1H), 7.29 (m, 2H) Mass Spectral Analysis, m/z ESI 625 (M+H⁺)

Preparation of 4.3

To a solution of 4.2 (2.18 g, 3.49 mmol) in methanol (75 mL) was added a1M solution of hydrogen chloride in diethyl ether (14 mL, 14 mmol) andthe mixture was heated to reflux for 2 hours. The solvents were removedunder vacuum and the residue taken up in ethyl acetate (75 mL). Asaturated aqueous solution of sodium bicarbonate (100 mL) was then addedto the mixture which was stirred for 2 hours at room temperature. Thelayers were separated and the organic layer was washed with water,brine, dried over sodium sulfate, filtered and concentrated underreduced pressure. The product was washed with hexanes and used in thenext step without further purification. Yield: 99% ¹H NMR (400 MHz,CDCl₃) δ: 0.67 (d, J=7 Hz, 3H), 1.28 (s, 3H), 1.92 (m, 3H), 2.75 (dd,J=13 Hz and 2 Hz, 1H), 3.08 (d, J=13 Hz, 0.5H), 3.11 (d, J=6 Hz, 0.5H),3.21 (d, J=6 Hz, 1H), 3.27 (m, 2H), 3.55 (dd, J=11 Hz and 6 Hz, 1H),3.74 (s, 3H), 4.88 (q, J=6 Hz, 1H), 6.64 (dd, J=8 Hz and 2 Hz, 1H), 6.70(s, 1H), 6.77 (d, J=7 Hz, 1H), 7.15 (m, 3H), 7.21 (m, 2H), 7.31 (m, 3H)Mass Spectral Analysis, m/z ESI 411 (M+H⁺)

Preparation of 4.4

A solution of 4.3 (1.42 g, 3.46 mmol) in toluene (200 mL) was heated toreflux for 60 hours. The mixture was concentrated under reducedpressure. The crude product was purified by column chromatography(eluent: dichloromethane/methanol mixtures of increasing polarity).Yield 38% ¹H NMR (400 MHz, CDCl₃) δ: 0.59 (d, J=7 Hz, 3H), 1.21 (s, 3H),2.00 (m, 1H), 2.16 (m, 1H), 2.87 (dd, J=14 Hz and 3 Hz, 1H), 3.05 (d,J=11 Hz, 1H), 3.20 (t, J=4 Hz, 2H), 4.38 (m, 2H), 6.31 (br s, 1H), 6.64(m, 1H), 6.69 (m, 1H), 6.76 (d, J=8 Hz, 1H), 7.17 (t, J=8 Hz, 2H), 7.21(dd, J=8 Hz and 2 Hz, 2H), 7.31 (t, J=7 Hz, 1H), 7.36 (m, 2H)

Mass Spectral Analysis, m/z ESI 377 (M−H⁺)

Preparation of 4

To a solution of 4.4 (0.50 g, 1.32 mmol) in anhydrous tetrahydrofuran(10 mL) was added borane-dimethyl sulfide complex (2M solution intetrahydrofuran, 4 mL, 8 mmol) and the reaction heated to reflux under anitrogen atmosphere for 16 hours. The mixture was then cooled to 0° C.Methanol (20 mL) was added to the reaction mixture, which was stirred at0° C. for 1 hour. A 2M anhydrous solution of hydrogen chloride indiethyl ether (5 mL) was then added to the reaction mixture, which wasthen heated to reflux for 1 hour. After cooling to room temperature, anaqueous ammonium hydroxide solution (5 mL) was added to the mixture,which was stirred for 10 minutes at room temperature. The mixture wasconcentrated under reduced pressure. The residue was dissolved inmethanol and concentrated under reduced pressure. This process wasrepeated 3 times. The crude product was purified by columnchromatography (eluent: dichloromethane/methanol/ammonium hydroxidemixtures of increasing polarity). Yield: 43% ¹H NMR (400 MHz, CD₃OD) δ:0.67 (d, J=7 Hz, 3H), 1.29 (s, 3H), 1.43 (d, J=8 Hz, 1H), 1.79 (t, J=12Hz, 1H), 1.87 (t, J=11 Hz, 1H), 1.96 (m, 3H), 2.25 (dt, J=13 Hz and 3Hz, 1H), 2.40 (dd, J=12 Hz and 2 Hz, 1H), 2.52 (d, J=12 Hz, 1H), 2.56(m, 1H), 2.67 (m, 2H), 2.82 (dd, J=12 Hz and 2 Hz, 1H), 3.03 (m, 1H),6.52 (dd, J=8 Hz and 2 Hz, 1H), 6.64 (t, J=2 Hz, 1H), 6.68 (d, J=8 Hz,1H), 7.04 (t, J=8 Hz, 1H), 7.17 (d, J=7 Hz, 3H), 7.25 (t, J=7 Hz, 2H)Mass Spectral Analysis, m/z ESI 351 (M+H⁺)

Example 5 Preparation of 5.2

To a stirred solution of 2.3 (3.87 g, 8.36 mmol) in acetonitrile (40 mL)under a nitrogen atmosphere were added, sequentially,diisopropylethylamine (5.8 mL, 33.44 mmol), 5.1 (2.17 g, 10.03 mmol) andO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) (4.03 g, 12.54 mmol). The reaction mixture was stirred at roomtemperature overnight, poured into a saturated aqueous solution ofammonium chloride and extracted with ethyl acetate. The organic extractswere washed with brine, dried over sodium sulfate, filtered andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography (eluent: hexane/ethyl acetate mixtures ofincreasing polarity). Yield: 71% ¹H NMR (400 MHz, CDCl₃) δ: 0.19 (s,6H), 0.43 (d, J=7 Hz, 3H), 0.99 (s, 9H), 1.30 (s, 3H), 1.44 (s, 9H),1.98 (dd, J=14 Hz and 6 Hz, 2H), 2.14 (m, 1H), 2.79 (m, 1H), 3.05 (dd,J=14 Hz and 6 Hz, 1H), 3.22 (dd, J=14 Hz and 6 Hz, 1H), 3.74 (s, 3H),3.82 (dd, J=12 Hz and 4 Hz, 1H), 4.25 (q, J=6 Hz, 1H), 4.92 (m, 1H),6.55 (m, 1H), 6.68 (m, 1H), 6.72 (t, J=2 Hz, 1H), 6.81 (d, J=8 Hz, 1H),7.12 (m, 1H), 7.16 (t, J=8 Hz, 2H), 7.24 (m, 3H) Mass Spectral Analysis,m/z ESI 625 (M+H⁺)

Preparation of 5.3

To a solution of 5.2 (3.68 g, 5.90 mmol) in methanol (40 mL) was added a4M solution of hydrogen chloride in dioxane (5.9 mL, 23.6 mmol) and themixture was heated to reflux for 2 hours. The mixture was concentratedunder reduced pressure and the residue taken up in ethyl acetate (75mL). A saturated aqueous solution of sodium bicarbonate (100 mL) wasthen added to the mixture which was stirred for 2 hours at roomtemperature. The layers were separated and the organic layer was washedwith water, brine, dried over sodium sulfate, filtered and concentratedunder reduced pressure. The product was washed with hexanes and used forthe next step without further purification. Yield: 77% ¹H NMR (400 MHz,CDCl₃) δ: 0.68 (d, J=7 Hz, 3H), 1.28 (s, 3H), 1.73 (m, 1H), 1.86 (m,1H), 1.94 (m, 1H), 2.79 (dd, J=12 Hz and 2 Hz, 1H), 3.07 (dd, J=14 Hzand 8 Hz, 1H), 3.23 (dd, J=14 Hz and 6 Hz, 1H), 3.30 (dd, J=13 Hz and 3Hz, 1H), 3.59 (dd, J=12 Hz and 3 Hz, 1H), 3.75 (s, 3H), 4.96 (m, 1H),6.66 (m, 2H), 6.74 (d, J=9 Hz, 1H), 7.17 (m, 2H), 7.27 (m, 4H), 7.38 (d,J=9 Hz, 1H)

Mass Spectral Analysis, m/z ESI 411 (M+H⁺)

Preparation of 5.4

A solution of 5.3 (2.01 g, 4.90 mmol) in toluene (70 mL) was heated toreflux for 60 hours. The mixture was concentrated under reducedpressure. The crude product was purified by column chromatography(eluent: dichloromethane/methanol mixtures of increasing polarity).Yield 70% ¹H NMR (400 MHz, CD₃OD) δ: 0.17 (d, J=7 Hz, 3H), 0.98 (t, J=13Hz, 1H), 1.30 (s, 3H), 1.80 (d, J=12 Hz, 1H), 1.93 (m, 1H), 3.01 (dd,J=14 Hz and 5 Hz, 1H), 3.07 (dd, J=13 Hz and 3 Hz, 1H), 3.30 (m, 1H),4.07 (m, 1H), 4.24 (dd, J=13 Hz and 2 Hz, 1H), 4.43 (t, J=4 Hz, 1H),6.45 (m, 2H), 6.58 (dd, J=8 Hz and 2 Hz, 1H), 7.07 (t, J=8 Hz, 1H), 7.22(m, 5H) Mass Spectral Analysis, m/z ESI 377 (M−H⁺)

Preparation of 5

To a solution of 5.4 (1.29 g, 3.4 mmol) in anhydrous tetrahydrofuran (20mL) was added borane-dimethyl sulfide complex (2M solution intetrahydrofuran, 10.3 mL, 20.6 mmol) and the reaction heated to refluxunder a nitrogen atmosphere for 16 hours. The mixture was then cooled to0° C. Methanol (10 mL) was added to the reaction mixture which wasstirred at 0° C. for 1 hour. A 2M anhydrous solution of hydrogenchloride in diethyl ether (10 mL) was then added to the reactionmixture, which was heated to reflux for 1 hour. After cooling, aqueousammonium hydroxide solution (5 mL) was added to the mixture, which wasstirred for 10 minutes at room temperature. The mixture was concentratedunder reduced pressure. The residue was dissolved in methanol (10 mL)and concentrated under reduced pressure. This process was repeated 3times. The crude product was purified by column chromatography (eluent:dichloromethane/methanol/ammonium hydroxide mixtures of increasingpolarity). Yield: 80% ¹H NMR (400 MHz, CD₃OD) δ: 0.89 (d, J=7 Hz, 3H),1.33 (s, 3H), 1.56 (d, J=14 Hz, 1H), 2.06 (m, 2H), 2.29 (dd, J=12 Hz and3 Hz, 1H), 2.38 (dd, J=12 Hz and 2 Hz, 1H), 2.50 (m, 2H), 2.70 (dd, J=12Hz and 3 Hz, 1H), 2.92 (m, 2H), 3.10 (t, J=11 Hz, 1H), 3.38 (d, J=10 Hz,2H), 6.60 (dd, J=8 Hz and 2 Hz, 1H), 6.73 (t, J=2 Hz, 1H), 6.77 (d, J=8Hz, 1H), 7.12 (t, J=8 Hz, 1H), 7.23 (d, J=7 Hz, 3H), 7.30 (t, J=8 Hz,2H)

Mass Spectral Analysis, m/z ESI 351 (M+H⁺)

Example 6 Preparation of 6.2

To a stirred solution of 2.3 (2 g, 4.32 mmol) in acetonitrile (20 mL)under a nitrogen atmosphere were added, sequentially,diisopropylethylamine (3 mL, 17.28 mmol), 6.1 (1.08 g, 5.18 mmol) andO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) (2.08 g, 6.48 mmol). The reaction was stirred at room temperatureovernight, poured into a saturated aqueous solution of ammonium chlorideand extracted with ethyl acetate. The organic extracts were washed withbrine, dried over sodium sulfate, filtered and concentrated underreduced pressure. The crude product was purified by columnchromatography (eluent: hexane/ethyl acetate mixtures of increasingpolarity). Yield: 82% ¹H NMR (400 MHz, CDCl₃) δ: 0.18 (s, 6H), 0.50 (d,J=7 Hz, 3H), 0.98 (s, 9H), 1.04-1.16 (m, 2H), 1.19-1.28 (m, 2H), 1.34(s, 3H), 1.50 (s, 9H), 1.59 (s, 2H), 1.60-1.69 (m, 2H), 1.70-1.84 (m,3H), 2.00 (m, 2H), 2.34 (t, J=13 Hz, 1H), 2.92 (dt, J=14 Hz and 4 Hz,1H), 3.73 (s, 3H), 3.96 (br s, 1H), 4.38 (dd, J=11 Hz and 6 Hz, 1H),4.54 (dd, J=9 Hz and 5 Hz, 1H), 6.67 (dd, J=8 Hz and 2 Hz, 1H), 6.74 (t,J=2 Hz, 1H), 6.86 (dd, J=9 Hz and 1 Hz, 1H), 7.13 (t, J=8 Hz, 1H)

Mass Spectral Analysis, m/z ESI 617 (M+H⁺)

Preparation of 6.3

To a solution of 6.2 (2.17 g, 3.52 mmol) in methanol (80 mL) was added a4M anhydrous solution of hydrogen chloride in dioxane (5 mL, 20 mmol)and the mixture was heated to reflux for 2 hours. The mixture wasconcentrated under reduced pressure and the residue taken up in ethylacetate (75 mL). To this was added a saturated aqueous solution ofsodium bicarbonate (100 mL), which was stirred for 2 hours at roomtemperature. The layers were separated and the organic layer was washedwith water, saturated brine, dried over sodium sulfate and concentratedunder reduced pressure. The product was washed with hexanes and used forthe next step without further purification. Yield: 97% ¹H NMR (400 MHz,CDCl₃) δ: 0.72 (d, J=7 Hz, 3H), 1.02-1.16 (m, 3H), 1.18-1.23 (m, 1H),1.30 (s, 3H), 1.64 (m, 4H), 1.76 (m, 3H), 1.81-1.89 (m, 1H), 1.93 (m,1H), 1.99 (m, 1H), 2.84 (dd, J=13 Hz and 2 Hz, 1H), 3.32 (dd, J=12 Hzand 3 Hz, 1H), 3.63 (dd, J=10 Hz and 6 Hz, 1H), 3.76 (s, 3H), 4.56 (dd,J=9 Hz and 5 Hz, 1H), 6.65 (dd, J=7 Hz and 2 Hz, 1H), 6.72 (t, J=2 Hz,1H), 6.79 (d, J=8 Hz, 1H), 7.16 (t, J=8 Hz, 1H), 7.44 (d, J=9 Hz, 1H)Mass Spectral Analysis, m/z ESI 403 (M+H⁺)

Preparation of 6.4

A solution of 6.3 (1.37 g, 3.41 mmol) in o-xylene (100 mL) was heated toreflux for 60 hours. The mixture was concentrated under reducedpressure. The crude product was purified by column chromatography(eluent: dichloromethane/methanol mixtures of increasing polarity).Yield 37% ¹H NMR (400 MHz, DMSO-D₆) δ: 0.49 (d, J=7 Hz, 3H), 1.00-1.29(m, 6H), 1.34 (s, 3H), 1.45 (m, 1H), 1.53 (d, J=8 Hz, 1H), 1.62 (d, J=8Hz, 1H), 1.72 (t, J=8 Hz, 1H), 1.84 (m, 1H), 1.96 (t, J=13 Hz, 1H), 2.10(m, 1H), 2.50 (m, 1H), 3.12 (dd, J=14 Hz and 3 Hz, 1H), 3.74 (t, J=2 Hz,1H), 4.15 (dd, J=12 Hz and 2 Hz, 1H), 4.24 (dd, J=13 Hz and 2 Hz, 1H),6.57 (dd, J=8 Hz and 1 Hz, 1H), 6.65 (d, J=2 Hz, 1H), 6.69 (d, J=8 Hz,1H), 7.11 (t, J=8 Hz, 1H), 8.24 (d, J=3 Hz, 1H), 9.24 (s, 1H) MassSpectral Analysis, m/z ESI 369 (M−H⁺)

Preparation of 6

To a solution of 6.4 (0.47 g, 1.27 mmol) in anhydrous tetrahydrofuran(10 mL) was added borane-dimethyl sulfide complex (2M solution intetrahydrofuran, 3.8 mL, 7.6 mmol) and the reaction heated to refluxunder a nitrogen atmosphere for 16 hours. The mixture was then cooled to0° C. Methanol (10 mL) was added to the reaction mixture which wasstirred at 0° C. for 1 hour. A 2M anhydrous solution of hydrogenchloride in diethyl ether (5 mL) was then added to the reaction mixture,which was heated to reflux for 1 hour. After cooling, aqueous ammoniumhydroxide solution (5 mL) was added to the mixture, which was stirredfor 10 minutes at room temperature. The mixture was concentrated underreduced pressure. The residue was dissolved in methanol (10 mL) andconcentrated under reduced pressure. This process was repeated 3 times.The crude product was purified by column chromatography (eluent:dichloromethane/methanol/ammonium hydroxide mixtures of increasingpolarity). Yield: 68% ¹H NMR (400 MHz, CD₃OD) δ: 0.76 (d, J=7 Hz, 3H),1.12 (m, 2H), 1.25 (m, 2H), 1.34 (m, 4H), 1.47 (m, 1H), 1.56 (d, J=13Hz, 1H), 1.70 (d, J=10 Hz, 1H), 1.84 (m, 5H), 2.09 (m, 2H), 2.46 (m,1H), 2.59 (dd, J=11 Hz and 2 Hz, 1H), 2.77 (m, 2H), 2.93 (m, 2H), 3.13(dd, J=12 Hz and 3 Hz, 1H), 6.59 (dd, J=8 Hz and 2 Hz, 1H), 6.73 (m,2H), 7.10 (t, J=8 Hz, 1H) Mass Spectral Analysis, m/z ESI 343 (M+H⁺)

Example 7 Preparation of 7.2

To a stirred solution of 2.3 (5 g, 10.8 mmol) in acetonitrile (50 mL)under a nitrogen atmosphere was added, sequentially, triethylamine (4mL, 32.4 mmol), 7.1 (2.7 g, 12.96 mmol) andO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) (5.2 g, 16.2 mmol). The reaction mixture was stirred at roomtemperature overnight, poured into a saturated aqueous solution ofammonium chloride and extracted with ethyl acetate. The organic extractswere washed with brine, dried over sodium sulfate, filtered andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography (eluent: hexane/ethyl acetate mixtures ofincreasing polarity). Yield: 60% ¹H NMR (400 MHz, CDCl₃) δ: 0.18 (s,6H), 0.47 (m, 3H), 0.88 (m, 1H), 0.98 (s, 9H), 1.14 (s, 2H), 1.24 (m,4H), 1.47 (s, 9H), 1.64 (s, 1H), 1.89 (m, 1H), 2.01 (m, 0.5H), 2.35 (m,0.5H), 2.47 (m, 0.5H), 2.56 (m, 0.5H), 2.70 (t, J=7 Hz, 1H), 3.36 (m,1H), 3.54 (m, 1H), 3.89 (m, 1H), 4.11 (m, 2H), 4.46 (m, 0.5H), 4.61 (m,2H), 4.96 (m, 0.5H), 6.65 (m, 2H), 6.77 (m, 1H), 6.90 (m, 1H), 7.13 (m,1H), 7.30 (m, 4H)

Mass Spectral Analysis, m/z ESI 654 (M+H⁺)

Preparation of 7.3

To a solution of 7.2 (4.15 g, 6.36 mmol) in ethanol (100 mL) was added a4M anhydrous solution of hydrogen chloride in dioxane (60 mL, 240 mmol)and the mixture was stirred at room temperature for 18 hours. Themixture was concentrated under reduced pressure and the residue taken upin ethyl acetate (75 mL). A saturated aqueous solution of sodiumbicarbonate (100 mL) was added, which was stirred for 2 hours at roomtemperature. The layers were separated and the organic layer was washedwith water, brine, dried over sodium sulfate, filtered and concentratedunder reduced pressure. The product was washed with hexanes and used forthe next step without further purification. Yield: 92% ¹H NMR (400 MHz,CDCl₃) δ: 0.65 (d, J=7 Hz, 2H), 0.69 (d, J=7 Hz, 1H), 1.23 (m, 5.5H),1.38 (m, 0.5H), 1.46 (m, 1H), 1.50 (m, 0.5H), 1.66 (d, J=13 Hz, 0.5H),1.82 (m, 0.5H), 1.90 (m, 0.5H), 2.08 (m, 1H), 2.20 (t, J=13 Hz, 0.5H),2.47 (m, 0.5H), 2.59 (m, 1H), 2.67 (m, 1H), 2.81 (m, 0.5H), 2.86 (m,1H), 3.27 (dd, J=14 Hz and 3 Hz, 0.5H), 3.37 (dd, J=14 Hz and 3 Hz,0.5H), 3.62 (m, 1H), 3.71 (m, 1H), 3.93 (dd, J=12 Hz and 3 Hz, 0.5H),4.11 (m, 2H), 4.63 (m, 2H), 6.66 (m, 2H), 6.75 (m, 1H), 7.14 (m, 1H),7.20 (m, 2H), 7.28 (m, 3H) Mass Spectral Analysis, m/z ESI 439 (M+H⁺)

Preparation of 7.4

A solution of 7.3 (2.58 g, 5.89 mmol) in o-xylene (200 mL) was heated toreflux for 60 hours. The mixture was concentrated under reducedpressure. The crude product was purified by column chromatography(eluent: dichloromethane/methanol mixtures of increasing polarity).Yield 25% ¹H NMR (400 MHz, DMSO-D₆) δ: 0.52 (d, J=7 Hz, 2H), 0.63 (d,J=7 Hz, 1H), 1.36 (s, 1H), 1.41 (s, 2H), 2.02 (m, 2H), 2.68 (m, 2H),3.12 (m, 0.5H), 3.46 (m, 1H), 3.55 (m, 1H), 3.63 (dd, J=14 Hz and 4 Hz,1H), 3.86 (dd, J=14 Hz and 6 Hz, 1H), 4.22 (m, 0.5H), 4.54 (m, 1H), 4.63(dd, J=12 Hz and 3 Hz, 1H), 4.75 (d, J=14 Hz, 1H), 6.70 (m, 1H), 6.78(m, 1H), 7.11 (m, 3H), 7.29 (m, 2H), 7.34 (m, 2H) Mass SpectralAnalysis, m/z ESI 391 (M−H⁺)

Preparation of 7

To a solution of 7.4 (0.57 g, 1.45 mmol) in anhydrous tetrahydrofuran(20 mL) was added borane-dimethyl sulfide complex (2M solution intetrahydrofuran, 5 mL, 10 mmol) and the reaction heated to reflux undera nitrogen atmosphere for 16 hours. The mixture was then cooled to 0° C.Methanol (20 mL) was added to the reaction mixture which was stirred at0° C. for 1 hour. A 2M anhydrous solution of hydrogen chloride indiethyl ether (10 mL) was then added to the reaction mixture, which washeated to reflux for 1 hour. After cooling, aqueous ammonium hydroxidesolution (10 mL) was added to the mixture, which was stirred for 10minutes at room temperature. The mixture was concentrated under reducedpressure. The residue was dissolved in methanol (10 mL) and concentratedunder reduced pressure. This process was repeated 3 times. The crudeproduct was purified by column chromatography (eluent:dichloromethane/methanol/ammonium hydroxide mixtures of increasingpolarity). Yield: 10% ¹H NMR (400 MHz, CD₃OD) δ: 0.71 (d, J=7 Hz, 3H),1.27 (m, 2H), 1.58 (m, 0.5H), 1.84 (m, 2H), 1.95 (m, 2H), 2.60 (m, 4H),2.73 (m, 2H), 2.81 (m, 2H), 2.88 (m, 1H), 3.56 (m, 0.5H) 3.69 (q, J=13Hz, 2H), 6.65 (dd, J=8 Hz and 2 Hz, 1H), 6.69 (s, 1H), 7.07 (t, J=8 Hz,1H), 7.24 (m, 1H), 7.31 (t, J=8 Hz, 2H), 7.37 (m, 1H)

Mass Spectral Analysis, m/z ESI 365 (M+H⁺)

Examples 8A-8AQ Preparation of 8A

To a 10 μM solution of compound 2.7 (1000 in methanol/acetic acid (8:1)was added tetramethyl orthoformate (TMOF) (100 μl) and a 12 μM solutionof aldehyde 8.1a (100 μl) in methanol/acetic acid (8:1). The reactionmixture was shaken for 16 hours. To this was added resin boundcyanoborohydride and shaking continued for 60 hours. The reactionmixture was filtered through SCX-2 cartridge and washed with methanol.The product was eluted from the cartridge by washing with a 2M solutionof ammonia in methanol solution. The product was purified by liquidchromatographic methods.

Mass Spectral Analysis, m/z ESI 381 (M+H⁺)

Preparation of 8B

8B was obtained according to a procedure similar to the one describedfor 8A, with the following exception: Aldehyde 8.1a was replaced withaldehyde 8.1b.

Mass Spectral Analysis, m/z ESI 352 (M+H⁺)

Preparation of 8C

8C was obtained according to a procedure similar to the one describedfor 8A, with the following exception: Aldehyde 8.1a was replaced withaldehyde 8.1c.

Mass Spectral Analysis, m/z ESI 357 (M+H⁺)

Preparation of 8D

8D was obtained according to a procedure similar to the one describedfor 8A, with the following exception: Aldehyde 8.1a was replaced withaldehyde 8.1d.

Mass Spectral Analysis, m/z ESI 365 (M+H⁺)

Preparation of 8E

8E was obtained according to a procedure similar to the one describedfor 8A, with the following exception: Aldehyde 8.1a was replaced withaldehyde 8.1e.

Mass Spectral Analysis, m/z ESI 379 (M+H⁺)

Preparation of 8F

8F was obtained according to a procedure similar to the one describedfor 8A, with the following exception: Aldehyde 8.1a was replaced withaldehyde 8.1f.

Mass Spectral Analysis, m/z ESI 357 (M+H⁺)

Preparation of 8G

8G was obtained according to a procedure similar to the one describedfor 8A, with the following exception: Aldehyde 8.1a was replaced withaldehyde 8.1g.

Mass Spectral Analysis, m/z ESI 341 (M+H⁺)

Preparation of 8H

8H was obtained according to a procedure similar to the one describedfor 8A, with the following exception: Aldehyde 8.1a was replaced withaldehyde 8.1h.

Mass Spectral Analysis, m/z ESI 352 (M+H⁺)

Preparation of 8I

8I was obtained according to a procedure similar to the one describedfor 8A, with the following exception: Aldehyde 8.1a was replaced withaldehyde 8.1i.

Mass Spectral Analysis, m/z ESI 407 (M+H⁺)

Preparation of 8J

8J was obtained according to a procedure similar to the one describedfor 8A, with the following exception: Aldehyde 8.1a was replaced withaldehyde 8.1j.

Mass Spectral Analysis, m/z ESI 365 (M+H⁺)

Preparation of 8K

8K was obtained according to a procedure similar to the one describedfor 8A, with the following exception: Aldehyde 8.1a was replaced withaldehyde 8.1k.

Mass Spectral Analysis, m/z ESI 443 (M+H⁺)

Preparation of 8L

8L was obtained according to a procedure similar to the one describedfor 8A, with the following exception: Aldehyde 8.1a was replaced withaldehyde 8.1l.

Mass Spectral Analysis, m/z ESI 352 (M+H⁺)

Preparation of 8M

8M was obtained according to a procedure similar to the one describedfor 8A, with the following exception: Aldehyde 8.1a was replaced withaldehyde 8.1m.

Mass Spectral Analysis, m/z ESI 385 (M+H⁺)

Preparation of 8N

8N was obtained according to a procedure similar to the one describedfor 8A, with the following exception: Aldehyde 8.1a was replaced withaldehyde 8.1n.

Mass Spectral Analysis, m/z ESI 365 (M+H⁺)

Preparation of 8O

80 was obtained according to a procedure similar to the one describedfor 8A, with the following exception: Aldehyde 8.1a was replaced withaldehyde 8.1o.

Mass Spectral Analysis, m/z ESI 443 (M+H⁺)

Preparation of 8P

8P was obtained according to a procedure similar to the one describedfor 8A, with the following exception: Aldehyde 8.1a was replaced withaldehyde 8.1p. Mass Spectral Analysis, m/z ESI 357 (M+H⁺)

Preparation of 8Q

8Q was obtained according to a procedure similar to the one describedfor 8A, with the following exception: Aldehyde 8.1a was replaced withaldehyde 8.1q. Mass Spectral Analysis, m/z ESI 381 (M+H⁺)

Preparation of 8R

8R was obtained according to a procedure similar to the one describedfor 8A, with the following exception: Aldehyde 8.1a was replaced withaldehyde 8.1r.

Mass Spectral Analysis, m/z ESI 379 (M+H⁺)

Preparation of 8S

8S was obtained according to a procedure similar to the one describedfor 8A, with the following exception: Aldehyde 8.1a was replaced withaldehyde 8.1s.

Mass Spectral Analysis, m/z ESI 401 (M+H⁺)

Preparation of 8T

8T was obtained according to a procedure similar to the one describedfor 8A, with the following exception: Aldehyde 8.1a was replaced withaldehyde 8.1t.

Mass Spectral Analysis, m/z ESI 367 (M+H⁺)

Preparation of 8U

8U was obtained according to a procedure similar to the one describedfor 8A, with the following exception: Aldehyde 8.1a was replaced withaldehyde 8.1u.

Mass Spectral Analysis, m/z ESI 393 (M+H⁺)

Preparation of 8V

8V was obtained according to a procedure similar to the one describedfor 8A, with the following exception: Aldehyde 8.1a was replaced withaldehyde 8.1v.

Mass Spectral Analysis, m/z ESI 341 (M+H⁺)

Preparation of 8W

8W was obtained according to a procedure similar to the one describedfor 8A, with the following exception: Aldehyde 8.1a was replaced withaldehyde 8.1w. Mass Spectral Analysis, m/z ESI 385 (M+H⁺)

Preparation of 8X

8X was obtained according to a procedure similar to the one describedfor 8A, with the following exception: Aldehyde 8.1a was replaced withaldehyde 8.1x.

Mass Spectral Analysis, m/z ESI 367 (M+H⁺)

Preparation of 8Y

8Y was obtained according to a procedure similar to the one describedfor 8A, with the following exception: Aldehyde 8.1a was replaced withaldehyde 8.1y.

Mass Spectral Analysis, m/z ESI 385 (M+H⁺)

Preparation of 8Z

8Z was obtained according to a procedure similar to the one describedfor 8A, with the following exception: Aldehyde 8.1a was replaced withaldehyde 8.1z.

Mass Spectral Analysis, m/z ESI 401 (M+H⁺)

Preparation of 8AA

8AA was obtained according to a procedure similar to the one describedfor 8A, with the following exception: Aldehyde 8.1a was replaced withaldehyde 8.1aa.

Mass Spectral Analysis, m/z ESI 457 (M+H⁺)

Preparation of 8AB

8AB was obtained according to a procedure similar to the one describedfor 8A, with the following exception: Aldehyde 8.1a was replaced withaldehyde 8.1ab.

Mass Spectral Analysis, m/z ESI 428 (M+H⁺)

Preparation of 8AC

8AC was obtained according to a procedure similar to the one describedfor 8A, with the following exception: Aldehyde 8.1a was replaced withaldehyde 8.1ac. Mass Spectral Analysis, m/z ESI 419 (M+H⁺)

Preparation of 8AD

8AD was obtained according to a procedure similar to the one describedfor 8A, with the following exception: Aldehyde 8.1a was replaced withaldehyde 8.1ad.

Mass Spectral Analysis, m/z ESI 402 (M+H⁺)

Preparation of 8AE

8AE was obtained according to a procedure similar to the one describedfor 8A, with the following exception: Aldehyde 8.1a was replaced withaldehyde 8.1ae.

Mass Spectral Analysis, m/z ESI 428 (M+H⁺)

Preparation of 8AF

8AF was obtained according to a procedure similar to the one describedfor 8A, with the following exception: Aldehyde 8.1a was replaced withaldehyde 8.1af.

Mass Spectral Analysis, m/z ESI 457 (M+H⁺)

Preparation of 8AG

8AG was obtained according to a procedure similar to the one describedfor 8A, with the following exception: Aldehyde 8.1a was replaced withaldehyde 8.1ag.

Mass Spectral Analysis, m/z ESI 428 (M+H⁺)

Preparation of 8AH

8AH was obtained according to a procedure similar to the one describedfor 8A, with the following exception: Aldehyde 8.1a was replaced withaldehyde 8.1ah.

Mass Spectral Analysis, m/z ESI 409 (M+H⁺)

Preparation of 8AI

8AI was obtained according to a procedure similar to the one describedfor 8A, with the following exception: Aldehyde 8.1a was replaced withaldehyde 8.1ai.

Mass Spectral Analysis, m/z ESI 394 (M+H⁺)

Preparation of 8AJ

8AJ was obtained according to a procedure similar to the one describedfor 8A, with the following exception: Aldehyde 8.1a was replaced withaldehyde 8.1aj.

Mass Spectral Analysis, m/z ESI 428 (M+H⁺)

Preparation of 8AK

8AK was obtained according to a procedure similar to the one describedfor 8A, with the following exception: Aldehyde 8.1a was replaced withaldehyde 8.1ak.

Mass Spectral Analysis, m/z ESI 402 (M+H⁺)

Preparation of 8AL

8AL was obtained according to a procedure similar to the one describedfor 8A, with the following exception: Aldehyde 8.1a was replaced withaldehyde 8.1al.

Mass Spectral Analysis, m/z ESI 409 (M+H⁺)

Preparation of 8AM

8AM was obtained according to a procedure similar to the one describedfor 8A, with the following exception: Aldehyde 8.1a was replaced withaldehyde 8.1am.

Mass Spectral Analysis, m/z ESI 417 (M+H⁺)

Preparation of Example 8AN

8AN was obtained according to a procedure similar to the one describedfor 8A, with the following exception: Aldehyde 8.1a was replaced withaldehyde 8.1an.

Mass Spectral Analysis, m/z ESI 427 (M+H⁺)

Preparation of 8AO

8AO was obtained according to a procedure similar to the one describedfor 8A, with the following exception: Aldehyde 8.1a was replaced withaldehyde 8.1ao.

Mass Spectral Analysis, m/z ESI 402 (M+H⁺)

Preparation of 8AP

8AP was obtained according to a procedure similar to the one describedfor 8A, with the following exception: Aldehyde 8.1a was replaced withaldehyde 8.1ap.

Mass Spectral Analysis, m/z ESI 393 (M+H⁺)

Preparation of 8AQ

8AQ was obtained according to a procedure similar to the one describedfor 8A, with the following exception: Aldehyde 8.1a was replaced withaldehyde 8.1aq.

Mass Spectral Analysis, m/z ESI 367 (M+H⁺)

Example 9A Preparation of 9.2

To a stirred solution of 2.3 (2 g, 4.32 mmol) in acetonitrile (20 ml)under a nitrogen atmosphere was added, sequentially,diisopropylethylamine (3 ml, 17.28 mmol), 9.1 (0.87 g, 5.18 mmol) andO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) (2.08 g, 6.48 mmol). The reaction was stirred at room temperatureovernight, poured into saturated ammonium chloride solution andextracted with ethyl acetate. The organic extracts were washed withsaturated brine, dried over sodium sulfate and concentrated underreduced pressure. The crude product was purified by columnchromatography (eluent: hexane/ethyl acetate mixtures of increasingpolarity). Yield: 75%

¹H NMR (400 MHz, CDCl₃) δ: 0.18 (s, 6H), 0.50 (d, J=7 Hz, 3H), 0.90 (d,J=7 Hz, 3H), 0.98 (s, 12H), 1.34 (s, 3H), 1.49 (s, 9H), 1.61 (br s, 1H),2.05 (m, 2H), 2.19 (m, 1H), 2.36 (t, J=13 Hz, 1H), 2.93 (dd, J=14 Hz and11 Hz, 1H), 3.74 (s, 3H), 4.40 (dd, J=12 Hz and 6 Hz, 1H), 4.56 (dd, J=9Hz and 5 Hz, 1H), 6.67 (dd, J=8 Hz and 2 Hz, 1H), 6.75 (t, J=2 Hz, 1H),6.87 (d, J=8 Hz, 1H), 7.13 (m, 1H). Mass Spectral Analysis, m/z ESI 577(M+H⁺)

Preparation of 9.3

To a solution of 9.2 (1.85 g, 3.20 mmol) in methanol (50 ml) was added4M hydrochloric acid in dioxane (5 ml, 20 mmol) and the mixture washeated to reflux for 2 hours. The solvents were removed under vacuum andthe residue taken up in ethyl acetate (75 ml). This was then stirredover a solution of saturated sodium hydrogen carbonate (100 ml) for 2hours. The layers were separated and the organic layer was washed withwater, saturated brine, dried over sodium sulfate and concentrated underreduced pressure. The product was washed with hexanes and used in thenext step without further purification. Yield: 100%

¹H NMR (400 MHz, CDCl₃) δ: 0.71 (d, J=7 Hz, 3H), 0.94 (d, J=7 Hz, 3H),0.97 (d, J=7 Hz, 3H), 1.29 (s, 3H), 1.93 (m, 3H), 2.00 (d, J=8 Hz, 1H),2.21 (m, 1H), 2.83 (dd, J=13 Hz and 2 Hz, 1H), 3.32 (dd, J=12 Hz and 3Hz, 1H), 3.65 (t, J=8 Hz, 1H), 3.76 (s, 3H), 4.58 (dd, J=9 Hz and 5 Hz,1H), 6.65 (dd, J=8 Hz and 2 Hz, 1H), 6.72 (t, J=2 Hz, 1H), 6.78 (d, J=8Hz, 1H), 7.15 (t, J=8 Hz, 1H), 7.47 (d, J=9 Hz, 1H).

Mass Spectral Analysis, m/z ESI 363 (M+H⁺)

Preparation of 9.4

A solution of 9.3 (1.19 g, 3.30 mmol) in o-xylene (150 ml) was heated toreflux for 60 hours. Concentrated under reduced pressure. The crudeproduct was purified by column chromatography (eluent:dichloromethane/methanol mixtures of increasing polarity). Yield 43% ¹HNMR (400 MHz, CDCl₃) δ: 0.72 (d, J=7 Hz, 3H), 0.94 (d, J=7 Hz, 3H), 0.97(d, J=7 Hz, 3H), 1.32 (s, 3H), 1.99 (d, J=8 Hz, 2H), 2.32 (s, 0.5H),2.37 (s, 0.5H), 2.45 (s, 1H), 2.83 (dd, J=14 Hz and 3 Hz, 1H), 3.34 (m,1H), 3.64 (m, 1H), 4.58 (dd, J=9 Hz and 5 Hz, 1H), 6.66 (m, 1H), 6.72(m, 1H), 6.80 (d, J=8 Hz, 1H), 7.11 (m, 1H)

Mass Spectral Analysis, m/z ESI 329 (M−H⁺)

Preparation of 9.5

To a solution of 9.4 (0.47 g, 1.42 mmol) in anhydrous tetrahydrofuran(20 ml) was added borane-dimethyl sulfide complex (2M intetrahydrofuran, 4.3 ml, 8.6 mmol) and the reaction heated to refluxunder a nitrogen atmosphere for 16 hours. The mixture was then cooled to0° C. and methanol (20 ml) was added and the reaction stirred at 0° C.for 1 hour. A 2M hydrochloric acid in diethyl ether solution (10 ml) wasthen added and the reaction heated to reflux for 1 hour. After cooling,aqueous ammonium hydroxide solution (5 ml) was added and the mixturestirred for 10 minutes. Concentrated under reduced pressure. The residuewas dissolved in methanol and concentrated under reduced pressure (×3).The crude product was purified by column chromatography (eluent:dichloromethane/methanol/ammonium hydroxide mixtures of increasingpolarity). Yield: 22%

¹H NMR (400 MHz, CD₃OD) δ: 0.75 (d, J=7 Hz, 3H), 0.94 (d, J=7 Hz, 3H),0.98 (d, J=7 Hz, 3H), 1.34 (s, 3H), 1.47 (d, J=13 Hz, 1H), 1.58 (sx, J=7Hz, 1H), 1.83 (d, J=8 Hz, 1H), 1.88 (t, J=9 Hz, 1H), 2.03 (m, 1H), 2.26(m, 1H), 2.55 (m, 3H), 2.72 (dd, J=12 Hz and 3 Hz, 1H), 2.79 (dd, J=11Hz and 3 Hz, 1H), 2.88 (dd, J=12 Hz and 3 Hz, 1H), 6.57 (dd, J=8 Hz and3 Hz, 1H), 6.70 (d, J=2 Hz, 1H), 6.73 (d, J=8 Hz, 1H), 7.09 (t, J=8 Hz,1H)

Mass Spectral Analysis, m/z ESI 303 (M+H⁺)

Preparation of 9A

To a solution of 9.5 (0.13 g, 0.4 mmol) in dichloromethane (5 mL) wasadded 9.6 (0.077 g, 0.47 mmol), 2-bromo-1-ethylpyridiniumtetrafluoroborate (0.13 g, 0.47 mmol) and diisopropylethylamine (0.32mL, 1.4 mmol) and the reaction mixture stirred at room temperatureovernight, poured into water and extracted with dichloromethane. Thecombined organic extracts were washed with water, saturated brinesolution, dried over sodium sulfate and concentrated under vacuum. Thecrude product was purified by HPLC. Yield: 2%

¹H NMR (400 MHz, CD₃OD), δ 0.70 (d, J=7 Hz, 3H), 0.83 (d, J=7 Hz, 3H),0.93 (d, J=7 Hz, 3H), 1.29 (m, 1H), 1.32 (s, 3H), 1.52 (d, J=12 Hz, 1H),1.97 (m, 1H), 2.03 (m, 1H), 2.11 (q, J=12 Hz, 1H), 2.27 (dd, J=12 Hz and8 Hz, 1H), 2.58 (dd, J=12 Hz and 2 Hz, 1H), 2.64 (m, 2H), 2.76 (t, J=8Hz, 1H), 2.81 (m, 0.5H), 2.86 (m, 2H), 2.93 (m, 2H), 3.95 (br s, 1H),6.58 (q, J=7 Hz and 2 Hz, 1H), 6.67 (d, J=8 Hz, 2H), 6.72 (m, 2H), 7.06(d, J=8 Hz, 2H), 7.10 (t, J=8 Hz, 1H). Mass Spectral Analysis, m/z ESI451 (M+H⁺)

Example 9B Preparation of 9B

To a solution of 9.5 (0.13 g, 0.4 mmol) in dichloromethane (5 mL) wasadded 9.7 (0.077 g, 0.47 mmol), 2-bromo-1-ethylpyridiniumtetrafluoroborate (0.13 g, 0.47 mmol) and diisopropylethylamine (0.32mL, 1.4 mmol) and the reaction mixture stirred at room temperatureovernight, poured into water and extracted with dichloromethane. Thecombined organic extracts were washed with water, saturated brinesolution, dried over sodium sulfate and concentrated under vacuum. Thecrude product was partially purified by column chromatography (eluent:dichloromethane/methanol/ammonium hydroxide mixtures of increasingpolarity).

Mass Spectral Analysis, m/z ESI 578 (M+H⁺)

The partially purified material was then dissolved in methanol (3 mL)and 4M hydrochloric acid in dioxane (5 ml, 20 mmol) was added. Themixture was stirred at room temperature overnight. The solvents wereevaporated and the crude material was purified by HPLC. Yield: 7%

¹H NMR (CD₃OD), δ 0.81 (d, J=7 Hz, 3H), 0.94 (d, J=6 Hz, 3H), 1.08 (d,J=6 Hz, 3H), 1.50 (s, 3H), 2.05 (d, J=13 Hz, 1H), 2.35 (m, 2H), 2.50 (m,1H), 3.02 (t, J=14 Hz, 1H), 3.36 (m, 2H), 3.74 (m, 2H), 3.89 (m, 1H),3.99 (s, 2H), 4.36 (m, 1H), 4.46 (m, 2H), 4.53 (m, 1H), 6.66 (m, 2H),6.78 (m, 3H), 7.14 (q, J=8 Hz, 2H). Mass Spectral Analysis, m/z ESI 478(M+H⁺)

Biological Assays

TABLE 1 Table of Compounds Example Structure Name [M + H]⁺ 1

3-((2R,3R,7S,9αS)-2,3- dimethyl-7-phenyl- octahydro-1H-quinolizin-2-yl)phenol 336.2 2A

1-((7R,8R,9αR)-8-(3- hydroxyphenyl)-7,8- dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin- 2(6H)-yl)-2- phenylethanone 379.3 2B

3-((7R,8R,9αR)-7,8- dimethyl-2-phenethyl- octahydro-1H-pyrido[1,2-a]pyrazin-8-yl)phenol 365.3 2C

((7R,8R,9αR)-8-(3- hydroxyphenyl)-7,8- dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin- 2(6H)- yl)(phenyl)methanone 365.7 2D

3-((7R,8R,9αR)-2-benzyl- 7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8- yl)phenol 351.3 2E

3-((7R,8R,9αR)-7,8- dimethyl-2- (phenylsulfonyl)-octahydro-1H-pyrido[1,2- α]pyrazin-8-yl)phenol 401.8 2F

3-((7R,8R,9αR)-7,8- dimethyl-2-phenyl- octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol 337.7 3A

3-((3S,7R,8R,9αR)-7,8- dimethyl-3-phenyl- octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol 337.2 3B

3-((3S,7R,8R,9αR)-2,7,8- trimethyl-3-phenyl- octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol 351.3 3C

2-((3S,7R,8R,9αR)-8-(3- hydroxyphenyl)-7,8- dimethyl-3-phenyl-hexahydro-1H-pyrido[1,2- α]pyrazin-2(6H)-yl)acetic acid dihydrochloride395.8 3D

3-((3S,7R,8R,9αR)-8-(3- hydroxyphenyl)-7,8- dimethyl-3-phenyl-hexahydro-1H-pyrido[1,2- α]pyrazin-2(6H)- yl)propanoic aciddihydrochloride 409.8 3E

3-((3S,7R,8R,9αR)-2- benzyl-7,8-dimethyl-3- phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8- yl)phenol 427.4 3F

3-((3S,7R,8R,9αR)-2- benzyl-7,8-dimethyl-3- phenyl-octahydro-1H-pyrido[1,2-α]pyrazin-8- yl)benzamide 454.9 3G

3-((3S,7R,8R,9αR)-7,8- dimethyl-3-phenyl- octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)benzamide 364.8 4

3-((3S,7R,8R,9αR)-3- benzyl-7,8-dimethyl- octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol 351.2 5

3-((3R,7R,8R,9αR)-3- benzyl-7,8-dimethyl- octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol 351.2 6

3-((3S,7R,8R,9αR)-3- cyclohexyl-7,8-dimethyl- octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol 343.7 7

3-((8R,9R,10αR)-2-benzyl- 8,9-dimethyl- decahydropyrido[1,2-α][1,4]diazepin-9-yl)phenol 365.8 8A

3-((7R,8R,9αR)-2-(3- methoxybenzyl)-7,8- dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8- yl)phenol 381.5 8B

3-((7R,8R,9αR)-7,8- dimethy-2-(pydin-2- ylmethyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8- yl)phenol 352.4 8C

3-((7R,8R,9αR)-2- (cyclohexylmethyl)-7,8- dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8- yl)phenol 357.6 8D

3-((7R,8R,9αR)-7,8- dimethyl-2-(4- methylbenzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8- yl)phenol 365.5 8E

3-((7R,8R,9αR)-2-(2,5- dimethylbenzyl)-7,8- dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8- yl)phenol 379.4 8F

3-((7R,8R,9αR)-7,8- dimethyl-2-(thiophen-3- ylmethyl)-octahydro-1H-yl)phenol 357.4 8G

3-((7R,8R,9αR)-2-(furan-3- ylmethyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2- α]pyrazin-8-yl)phenol 341.1 8H

3-((7R,8R,9αR)-7,8- dimethyl-2-(pydin-3- ylmethyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8- yl)phenol 352.4 8I

3-((7R,8R,9αR)-2-(4-tert- butylbenzyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2- α]pyrazin-8-yl)phenol 407.6 8J

3-((7R,8R,9αR)-7,8- dimethyl-2-(2- methylbenzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8- yl)phenol 365.5 8K

3-((7R,8R,9αR)-7,8- dimethyl-2-(4- phenoxybenzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8- yl)phenol 443.4 8L

3-((7R,8R,9αR)-7,8- ylmethyl)-octahydro-1H- pyrido[1,2-α]pyrazin-8-yl)phenol 352.4 8M

3-((7R,8R,9αR)-2-(3- chlorobenzyl)-7,8- dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8- yl)phenol 385.4 8N

3-((7R,8R,9αR)-7,8- dimethyl-2-(3- methylbenzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8- yl)phenol 365.5 8O

3-((7R,8R,9αR)-7,8- dimethyl-2-(3- phenoxybenzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8- yl)phenol 443.5 8P

3-((7R,8R,9αR)-7,8- dimethyl-2-(thiophen-2- ylmethyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8- yl)phenol 357.4 8Q

3-((7R,8R,9αR)-2-(4- methoxybenzyl)-7,8- dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8- yl)phenol 381.4 8R

3-((7R,8R,9αR)-2-(4- ethylbenzyl)-7,8-dimethyl- octahydro-1H-pyrido[1,2-α]pyrazin-8-yl)phenol 379.5 8S

3-((7R,8R,9αR)-7,8- dimethyl-2-(naphthalen-1- ylmethyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8- yl)phenol 401.5 8T

2-(((7R,8R,9αR)-8-(3- hydroxyphenyl)-7,8- dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin- 2(6H)-yl)methyl)phenol 367.4 8U

3-((7R,8R,9αR)-2-(4- isopropylbenzyl)-7,8- dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8- yl)phenol 393.6 8V

3-((7R,8R,9αR)-2-(furan-2- ylmethyl)-7,8-dimethyl-octahydro-1H-pyrido[1,2- α]pyrazin-8-yl)phenol 341.4 8W

3-((7R,8R,9αR)-2-(2- chlorobenzyl)-7,8- dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8- yl)phenol 385.4 8X

3-((7R,8R,9αR)-2-(3- hydroxybenzyl)-7,8- dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8- yl)phenol 367.4 8Y

3-((7R,8R,9αR)-2-(4- chlorobenzyl)-7,8- dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8- yl)phenol 385.4 8Z

3-((7R,8R,9αR)-7,8- ylmethyl)-octahydro-1H- pyrido[1,2-α]pyrazin-8-yl)phenol 401.5 8AA

3-((7R,8R,9αR)-2-(3- (benzyloxy)benzyl)-7,8- dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8- yl)phenol 457.5 8AB

3-((7R,8R,9αR)-7,8- dimethyl-2-(4-(pyridin-4- yl)benzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8- yl)phenol 428.4 8AC

3-((7R,8R,9αR)-2-(2,3- dichlorobenzyl)-7,8- dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8- yl)phenol 419.3 8AD

3-((7R,8R,9αR)-7,8- dimethyl-2-(quinolin-2- ylmethyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8- yl)phenol 402.4 8AE

3-((7R,8R,9αR)-7,8- dimethyl-2-(2-(pyridin-4- yl)benzyl)-octahydro-1H-pyridol[2-α]pyrazin-8- yl)phenol 428.5 8AF

3-((7R,8R,9αR)-2-(4- (benzyloxy)benzyl)-7,8- dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8- yl)phenol 457.4 8AG

3-((7R,8R,9αR)-7,8- dimethyl-2-(3-(pyridin-4- yl)benzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8- yl)phenol 428.4 8AH

methyl 4-(((7R,8R,9αR)-8- (3-hydroxyphenyl)-7,8- dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin- 2(6H)-yl)methyl)benzoate 409.4 8AI

3-((7R,8R,9αR)-2-(4- (dimethylamino)benzyl)- 7,8-dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8- yl)phenol 394.8 8AJ

3-((7R,8R,9αR)-7,8- dimethyl-2-(4-(pyridin-3- yl)benzyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8- yl)phenol 428.4 8AK

34(7R,8R,9αR)-7,8- dimethyl-2-(quinolin-3- ylmethyl)-octahydro-1H-pyrido[1,2-α]pyrazin-8- yl)phenol 402.4 8AL

methyl 3-(((7R,8R,9αR)-8- (3-hydroxyphenyl)-7,8- dimethyl-hexahydro-1H-pyrido[1,2-α]pyrazin- 2(6H)-yl)methyl)benzoate 409.4 8AM

3-((7R,8R,9αR)-2-(4-(1H- imidazol-1-yl)benzyl)-7,8-dimethyl-octahydro-1H- pyrido[1,2-α]pyrazin-8- yl)phenol 417.4 8AN

3-((7R,8R,9αR)-2- dimethyl-octahydro-1H- pyrido[1,2-α]pyrazin-8-yl)phenol 427.4 8AO

3-((7R,8R,9αR)-7,8- ylmethyl)-octahydro-1H- pyrido[1,2-α]pyrazin-8-yl)phenol 402.4 8AP

3-((7R,8R,9αR)-7,8- dimethyl-2-(2,4,5- trimethylbenzyl)-octahydro-1H-pyrido[1,2- α]pyrazin-8-yl)phenol 393.5 8AQ

3-((7R,8R,9αR)-2-(4- hydroxybenzyl)-7,8- dimethyl-octahydro-1H-pyrido[1,2-α]pyrazin-8- yl)phenol 367.3 9A

3-(4-hydroxyphenyl)-1- ((3S,7R,8R,9αR)-8-(3- hydroxyphenyl)-3-isopropyl-7,8-dimethyl- hexahydro-1H-pyrido[1,2-α]pyrazin-2(6H)-yl)propan- 1-one 451.26 9B

((R)-7-hydroxy-1,2,3,4- tetrahydroisoquinolin-3-yl)((3S,7R,8R,9αR)-8-(3- hydroxyphenyl)-3- isopropyl-7,8-dimethyl-hexahydro-1H-pyrido[1,2- α]pyrazin-2(6H)- yl)methanone 478.20

Biological Methods

The potencies of the compounds were determined by testing the ability ofa range of concentrations of each compound to inhibit the binding of thenon-selective opioid antagonist, [³H]diprenorphine, to the cloned humanμ, κ, and δ opioid receptors, expressed in separate cell lines. IC₅₀values were obtained by nonlinear analysis of the data using GraphPadPrism version 3.00 for Windows (GraphPad Software, San Diego). K_(i)values were obtained by Cheng-Prusoff corrections of IC₅₀ values.

The receptor binding method (DeHaven and DeHaven-Hudkins, 1998) was amodification of the method of Raynor et al. (1994). After dilution inbuffer A and homogenization as before, membrane proteins (10-80 μg) in250 μL were added to mixtures containing test compound and[³H]diprenorphine (0.5 to 1.0 nM, 40,000 to 50,000 dpm) in 250 μL ofbuffer A in 96-well deep-well polystyrene titer plates (Beckman). Afterincubation at room temperature for one hour, the samples were filteredthrough GF/B filters that had been presoaked in a solution of 0.5% (w/v)polyethylenimine and 0.1% (w/v) bovine serum albumin in water. Thefilters were rinsed 4 times with 1 mL of cold 50 mM Tris HCl, pH 7.8 andradioactivity remaining on the filters determined by scintillationspectroscopy. Nonspecific binding was determined by the minimum valuesof the titration curves and was confirmed by separate assay wellscontaining 10 μM naloxone. K_(i) values were determined by Cheng-Prusoffcorrections of IC₅₀ values derived from nonlinear regression fits of 12point titration curves using GraphPad Prism® version 3.00 for Windows(GraphPad Software, San Diego, Calif.).

To determine the equilibrium dissociation constant for the inhibitors(K_(i)), radioligand bound (cpm) in the presence of variousconcentrations of test compounds was measured. The concentration to givehalf-maximal inhibition (EC₅₀) of radioligand binding was determinedfrom a best nonlinear regression fit to the following equation,

$Y = {{Bottom} + \frac{\left( {{Top} - {Bottom}} \right)}{1 + 10^{X - {{LogEC}\; 50}}}}$

where Y is the amount of radioligand bound at each concentration of testcompound, Bottom is the calculated amount of radioligand bound in thepresence of an infinite concentration of test compound, Top is thecalculated amount of radioligand bound in the absence of test compound,X is the logarithm of the concentration of test compound, and LogEC50 isthe log of the concentration of test compound where the amount ofradioligand bound is half-way between Top and Bottom. The nonlinearregression fit was performed using the program Prism® (GraphPadSoftware, San Diego, Calif.). The K_(i) values were then determined fromthe EC₅₀ values by the following equation,

$K_{i} = \frac{{EC}_{50}}{1 + \frac{\lbrack{ligand}\rbrack}{K_{d}}}$

where [ligand] is the concentration of radioligand and K_(d) is theequilibrium dissociation constant for the radioligand.

The potencies of the antagonists were assessed by their abilities toinhibit agonist-stimulated [³⁵S]GTPγS binding to membranes containingthe cloned human μ, κ, or δ opioid receptors. The agonists used wereloperamide for the μ opioid receptor.

To determine the IC₅₀ value, which was the concentration to givehalf-maximal inhibition of agonist-stimulated [³⁵S]GTPγS binding, theamount of [³⁵S]GTPγS bound in the presence of a fixed concentration ofagonist and various concentrations of antagonist was measured. The fixedconcentration of agonist was the EC₈₀ for the agonist, which was theconcentration to give 80% of the relative maximum stimulation of[³⁵S]GTPγS binding. The IC₅₀ value was determined from a best nonlinearregression fit of the data to the following equation,

$Y = {{Bottom} + \frac{\left( {{Top} - {Bottom}} \right)}{1 + 10^{X - {{LogIC}\; 50}}}}$

where Y is the amount of [³⁵S]GTPγS bound at each concentration ofantagonist, Bottom is the calculated amount of [³⁵S]GTPγS bound in thepresence of an infinite concentration of antagonist, Top is thecalculated amount of [³⁵S]GTPγS bound in the absence of addedantagonist, X is the logarithm of the concentration of antagonist, andLogIC₅₀ is the logarithm of the concentration of antagonist where theamount of [³⁵S]GTPγS bound is halfway between Bottom and Top. Thenonlinear regression fit was performed using GraphPad Prism® version3.00 for Windows (GraphPad Software, San Diego, Calif.).

The compounds described in Table 1 were tested for their affinitytowards the μ, δ and κ opioid receptors. All of these compounds bindwith affinity less than 100 μM to the μ, δ and κ opioid receptors. Thesecompounds displayed various degrees of selectivity μvs. δ, μ vs. κ and κvs. δ. The activity of selected ligands was also evaluated in vitro.Numerous compounds were found to be pure antagonist at the mu opioidreceptor (no agonist activity detectable at concentration >10 μM).Binding data (K_(i) values) and in vitro mu antagonist activities (IC₅₀)of selected compounds is indicated in Table 2.

TABLE 2 Opioid receptor (κ, μ, δ) binding data and in vitro antagonistactivity (μ) and of Examples 1, 2B, 2C, 2D, 3A, 3B and 4. K_(i)(μ)IC₅₀(μ) K_(i)(δ) K_(i)(κ) Example (nM) (nM) (nM) (nM) 1 0.57 0.53 30 8.92B 5.5 21 242 112 2C 2 21 25 190 2D 1.1 11 139 44 3A 3.6 12 88 18 3B 3.326 716 12 4 8.9 29 36 85

When ranges are used herein for physical properties, such as molecularweight, or chemical properties, such as chemical formulae, allcombinations and subcombinations of ranges and specific embodimentstherein are intended to be included.

The disclosures of each patent, patent application and publication citedor described in this document are hereby incorporated herein byreference, in their entirety.

Those skilled in the art will appreciate that numerous changes andmodifications can be made to the preferred embodiments of the inventionand that such changes and modifications can be made without departingfrom the spirit of the invention. It is, therefore, intended that theappended claims cover all such equivalent variations as fall within thetrue spirit and scope of the invention.

1. A compound of formula I:

wherein: R¹ is —C(═O)NR⁶R⁷; R² and R³ are each independently alkyl oralkenyl; R⁴ is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl,aralkyl, alkylaralkyl, or heteroarylalkyl; X is NR⁵; R⁵ is —C(═O)R^(8b);R⁶ is H, alkyl, cycloalkyl, alkylcycloalkyl, or aralkyl; R⁷ is H, alkyl,aralkyl, or aryl; R^(8b) is H, alkyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroarylalkyl, aralkyl, or aryl; m is 1; and n is 1, or apharmaceutically acceptable salt thereof.
 2. The compound of claim 1,wherein R⁶ is H or alkyl.
 3. The compound of claim 2, wherein R⁷ is H oralkyl.
 4. The compound of claim 1, having the structure of formula IIa:

wherein R⁶ and R⁷ are each independently alkyl; R² and R³ are eachindependently alkyl; and R^(8b) is heteroaryl, heteroarylalkyl, aralkyl,or aryl.
 5. The compound according to claim 4, having the structure offormula IIb:


6. The compound of claim 4, wherein R⁶ and R⁷ are each independentlymethyl.
 7. The compound of claim 4, wherein R^(8b) is aralkyl or aryl.8. The compound of claim 7, wherein R^(8b) is aryl and R⁶ and R⁷ areeach independently methyl.
 9. The compound of claim 8, wherein R^(8b) isaryl substituted with halo.
 10. The compound of claim 9, wherein R^(8b)is aryl substituted with fluoro.
 11. A method for binding delta opioidreceptors, comprising the step of: contacting one or more delta opioidreceptors with a compound of formula (I) or a salt thereof in an amounteffective to bind to the opioid receptor,

wherein: R¹ is —C(═O)NR⁶R⁷; R² and R³ are each independently alkyl oralkenyl; R⁴ is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl,aralkyl, alkylaralkyl, or heteroarylalkyl; X is NR⁵; R⁵ is —C(═O)R^(8b);R⁶ is H, alkyl, cycloalkyl, alkylcycloalkyl, or aralkyl; R⁷ is H, alkyl,aralkyl, or aryl; R^(8b) is H, alkyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroarylalkyl, aralkyl, or aryl; m is 1; and n is
 1. 12.The method of claim 11, wherein the compound has the structure offormula IIa:

wherein R⁶ and R⁷ are each independently alkyl; R² and R³ are eachindependently alkyl; and R^(8b) is heteroaryl, heteroarylalkyl, aralkyl,or aryl.
 13. The method of claim 12, wherein the compound has thestructure of formula IIb:


14. The method of claim 12, wherein R⁶ and R⁷ are each independentlymethyl.
 15. The method of claim 12, wherein R^(8b) is aralkyl or aryl.16. The method of claim 15, wherein R^(8b) is aryl and R⁶ and R⁷ areeach independently methyl.
 17. The method of claim 16, wherein R^(8b) isaryl substituted with halo.
 18. The method of claim 17, wherein R^(8b)is aryl substituted with fluoro.